Novel carboxylic acids and derivatives for the treatment of and preventing diabetes and dyslipidaemia

ABSTRACT

The present invention relates to a compound of the formula ((I): in which: n is an integer chosen from 1, 2 and 3; Y represents O; N—OR 9 , in which R 9  represents H or a saturated hydrocarbon-based aliphatic group; CR 10 R 11 , in which R 10  and R 11 , which may be identical or different, represent H or a saturated hydrocarbon-based aliphatic group; R 1  and R 2 , which may be identical or different, represent H or a saturated aliphatic hydrocarbon-based chain; or alternatively R 1  and R 2  together form an optionally substituted saturated aliphatic hydrocarbon-based chain; the radicals R 3  and R 4 , which may be identical or different, take any of the is meanings given above for R 1  and R 2 , or alternatively R 1  and the group R 4  borne by the carbon alpha to CR 1 R 2  represent nothing and a double bond links the CR 1 R 2  carbon to the alpha CR 3 R 4  carbon; or alternatively one of the radicals R 1  and R 2  forms with one of the radicals R 3  and R 4  an optionally substituted saturated or unsaturated aliphatic hydrocarbon-based chain; one of the radicals R 5  and R 6  represents W, and the other represents Z which is chosen from a saturated or unsaturated aliphatic hydrocarbon-based radical; an optionally substituted, saturated, unsaturated and/or aromatic carbocyclic or heterocyclic radical; a radical -alk-Cy, in which alk represents an alkylene chain and Cy represents an optionally substituted saturated, unsaturated and/or aromatic heterocyclic or carbocyclic radical; W represents —XL-CO 2 R 7 ; —X-L-Tet, in which X and L are as defined below and Tet represents optionally substituted tetrazole; in which L represents a saturated or unsaturated aliphatic hydrocarbon-based chain, which is optionally substituted and/or optionally interrupted by optionally substituted arylene; X represents O; NR 8 , in which R 8  represents H; a saturated aliphatic hydrocarbon-based group; a group —CO—R′ or —SO 2 —R′, in which R′ takes any of the meanings given below for R 7  with the exception of H; or R 8  represents an optionally substituted aromatic carbocyclic group; or X represent S(O) m , in which m is chosen from 0, 1 and 2; R 7  represents H; a saturated or unsaturated aliphatic hydrocarbon-based group; an optionally substituted, saturated, unsaturated and/or aromatic carbocyclic group; an optionally substituted, saturated, unsaturated and/or aromatic heterocyclic group; and the pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, and also mixtures thereof in all proportions, which can be used in the treatment of dyslipidaemia, atherosclerosis and diabetes.

The present invention relates to carboxylic acid derivatives that can beused in the treatment of dyslipidaemia, atherosclerosis and diabetes, topharmaceutical compositions comprising them and to processes for thepreparation of these compounds.

The invention also relates to the use of these compounds for theproduction of medicaments for the treatment of dyslipidaemia,atherosclerosis and diabetes.

In most countries, cardiovascular disease remains one of the majordiseases and the main cause of death. About one third of men develop amajor cardiovascular disease before the age of 60, with women showing alower risk (ratio of 1 to 10). With advancing years (after the age of65, women become just as vulnerable to cardiovascular diseases as men),this disease increases even more in scale. Vascular diseases, such ascoronary disease, strokes, restenosis and peripheral vascular diseaseremain the prime cause of death and handicap worldwide.

Whereas the diet and lifestyle can accelerate the development ofcardiovascular diseases, a genetic predisposition leading todyslipidaemia is a significant factor in cardiovascular accidents anddeath.

The development of atherosclerosis appears to be linked mainly todyslipidaemia, which means abnormal levels of lipoproteins in the bloodplasma. This dysfunction is particularly evident in coronary disease,diabetes and obesity.

The concept intended to explain the development of atherosclerosis wasmainly focused on the metabolism of cholesterol and on the metabolism oftriglycerides.

However, since the studies of Randle et al. (Lancet, 1963, 785-789), anovel concept has been proposed: a glucose-fatty acid cycle or Randlecycle, which describes the regulation of the equilibrium between themetabolism of lipids in terms of triglycerides and cholesterol, and theoxygenation of glucose. Following this concept, the inventors havedeveloped a novel programme, the aim of which is to find novel compoundsacting simultaneously on lipid metabolism and glucose metabolism.

Fibrates are well-known therapeutic agents with a mechanism of actionvia the “Peroxisome Proliferator Activated Receptors”. These receptorsare the main regulators of lipid metabolism in the liver (PPARαisoform). In the last 10 years, thiazolidinediones have been describedas powerful hypoglycaemiant agents in man and animals. It has beenreported that thiazolidinediones are powerful selective activators ofanother isoform of PPARs: PPARγ (Lehmann et al., J. Biol. Chem., 1995,270, 12953-12956).

The inventors have discovered a novel class of compounds that arepowerful activators of the PPARα and PPARγ isoforms. As a result of thisactivity, these compounds have a substantial hypolipidaemiant andhypoglycaemiant effect.

The compounds of the invention have the formula I:

in which:n is an integer chosen from 1, 2 and 3;Y represents O; N—OR⁹, in which R⁹ represents H or a saturatedhydrocarbon-based aliphatic group; CR¹⁰R¹¹, in which R¹⁰ and R¹¹, whichmay be identical or different, represent H or a saturatedhydrocarbon-based aliphatic group;R¹ and R², which may be identical or different, represent H or asaturated aliphatic hydrocarbon-based chain; or alternatively R¹ and R²together form an optionally substituted saturated aliphatichydrocarbon-based chain; the radicals R³ and R⁴, which may be identicalor different, take any of the meanings given above for R¹ and R², oralternativelyR¹ and the group R⁴ borne by the carbon alpha to CR¹R² represent nothingand a double bond links the CR¹R² carbon to the alpha CR³R⁴ carbon; oralternatively one of the radicals R¹ and R² forms with one of theradicals R³ and R⁴ an optionally substituted saturated or unsaturatedaliphatic hydrocarbon-based chain, such as alkylene or alkenylene;one of the radicals R⁵ and R⁶ represents W, and the other represents Zwhich is chosen from an optionally substituted saturated or unsaturatedaliphatic hydrocarbon-based radical; an optionally substituted,saturated, unsaturated and/or aromatic carbocyclic or heterocyclicradical; a radical -alk-Cy, in which alk represents an alkylene chainand Cy represents an optionally substituted saturated, unsaturatedand/or aromatic heterocyclic or carbocyclic radical;W represents —XL-CO₂R⁷; —X-L-Tet, in which X and L are as defined belowand Tet represents optionally substituted tetrazole;R⁷ represents H, a saturated or unsaturated aliphatic hydrocarbon-basedgroup, an optionally substituted, saturated, unsaturated and/or aromaticcarbocyclic group, or an optionally substituted, saturated, unsaturatedand/or aromatic heterocyclic group;X represents O; NR⁸, in which R⁸ represents H; a saturated aliphatichydrocarbon-based group; a group —CO—R′ or —SO₂—R′, in which R′ takesany of the meanings given above for R⁷ with the exception of H; or anoptionally substituted aromatic carbocyclic group;S(O)_(m), in which m is chosen from 0, 1 and 2;L represents a saturated or unsaturated aliphatic hydrocarbon-basedchain, which is optionally substituted and/or optionally interrupted byoptionally substituted arylene; and the pharmaceutically acceptablederivatives, salts, solvates and stereoisomers thereof, and alsomixtures thereof in all proportions.

Among the derivatives of the compounds of the formula I that areintended in particular are the salts.

Examples of salts include the pharmaceutically acceptable salts formedwith a pharmaceutically acceptable organic or mineral base or with apharmaceutically acceptable organic or mineral acid.

Examples of salts with organic or mineral bases that may be mentionedinclude the salts form with metals and especially alkali metals,alkaline-earth metals and transition metals (such as sodium, potassium,calcium, magnesium or aluminium), or with bases, for instance ammonia orsecondary or tertiary amines (such as diethylamine, triethylamine,piperidine, piperazine or morpholine) or with basic amino acids, or withosamines (such as meglumine) or with amino alcohols (such as3-aminobutanol and 2-aminoethanol).

Examples of salts with organic or mineral acids include thehydrochloride, hydrobromide, sulfate, hydrogen sulfate,dihydrogenphosphate, citrate, maleate, fumarate, 2-naphthalenesulfonateand para-toluenesulfonate.

The invention also covers the salts allowing a suitable separation orcrystallisation of the compounds of the formula I, such as picric acid,oxalic acid or an optically active acid, for example tartaric acid,dibenzoyltartaric acid, mandelic acid or camphorsulfonic acid. However,a preferred subgroup of salts consists of salts of the compounds of theformula I with pharmaceutically acceptable acids or bases.

The formula I also includes all the types of geometrical isomers andstereoisomers of the compounds of the formula I.

Thus, the invention is also directed towards the optically active forms(stereoisomers), enantiomers, racemic mixtures, diastereoisomers,hydrates and solvates of these compounds. The term “solvate” is thusdefined as covering the adducts of the compounds with inert solventmolecules, formed as a result of their mutual forces of attraction. Suchsolvates may be, for example, monohydrates, dihydrates, or alcoholates.

The term “pharmaceutically acceptable derivative” includes, for example,the salts of the compounds of the invention and the compounds alsoreferred to as “prodrugs”. The term “prodrug derivative” is defined asbeing the compounds of the formula I modified with, for example, alkylor acyl, sugar or oligopeptide groups, which are rapidly cleaved in thebody to form the active compounds according to the invention. They alsoinclude the biodegradable polymer derivatives of the compounds accordingto the invention.

The invention also relates to mixtures of the compounds of the formula Iaccording to the invention, for example mixtures of two diastereoisomersin ratios, such as 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000. Theyare preferably mixtures of stereoisomeric compounds.

The term “aliphatic hydrocarbon-based group” means a hydrocarbon-basedgroup having a linear or branched chain, preferably containing from 1 to14 carbon atoms, preferentially from 1 to 10 and better still from 1 to6 carbon atoms, for example from 1 to 4 carbon atoms.

Examples of saturated hydrocarbon-based aliphatic groups are alkylradicals, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl,hexyl, isohexyl, neohexyl, 1-methylpentyl, 3-methylpentyl,1,1-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl,1-methyl-1-ethylpropyl, heptyl, 1-methylhexyl, 1-propylbutyl,4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-methylhexyl,5,5-dimethylhexyl, nonyl, decyl, 1-methylnonyl, 3,7-dimethyloctyl and7,7-dimethyloctyl.

If the hydrocarbon-based aliphatic group is unsaturated, it may compriseone or two unsaturations. The unsaturations are either of ethylenic typeor of acetylenic type. The unsaturated chains contain at least twocarbon atoms.

Alkenyl and alkynyl groups are examples of unsaturated aliphatichydrocarbon-based groups.

Examples of unsaturated aliphatic hydrocarbon-based groups of alkenyltype include allyl, vinyl and —CH═CH—CH₃.

Examples of alkynyl groups include —(CH₂)_(n)—C≡C—R, n being an integerbetween 0 and 10 and R representing —(CH₂)_(m)—CH₃, in which m is aninteger between 0 and 10, or alternatively R represents H.

The expression “saturated or unsaturated aliphatic hydrocarbon-basedchain” means a divalent radical derived from a saturated, orunsaturated, aliphatic hydrocarbon-based group as defined above byreplacement of a hydrogen atom with a bond.

The saturated aliphatic hydrocarbon-based chains are termed “alkylene”if they contain no double bonds.

The unsaturated aliphatic hydrocarbon-based chains are termed“alkenylene” if they contain one or more unsaturations of ethylenictype.

In the context of the invention, the expression “saturated, unsaturatedand/or aromatic cyclic (carbocyclic or heterocyclic) radical” means thatthe same radical may comprise a saturated portion and/or an unsaturatedportion and/or an aromatic portion.

The carbocyclic and heterocyclic radicals include mono- and polycyclicradicals; these radicals preferably denote mono-, bi- or tricyclicradicals. In the case of polycyclic radicals, it should be understoodthat these radicals consist of monocycles fused in pairs (for exampleortho-fused or peri-fused), i.e. containing at least two carbon atoms incommon. Each monocycle is preferably 3- to 8-membered and better still5- to 7-membered.

The heterocyclic groups comprise hetero atoms generally chosen from O, Nand S optionally in oxidised form (in the case of S and N).

Each of the monocycles constituting the heterocycle preferably comprisesfrom 1 to 4 hetero atoms and better still from 1 to 3 hetero atoms.

Examples of aromatic monocyclic heterocyclic groups include 5- to7-membered monocyclic heteroaryls, such as pyridine, furan, thiophene,pyrrole, imidazole, thiazole, isoxazole, isothiazole, furazane,pyridazine, pyrazine, thiazines, oxazole, pyrazole, oxadiazole, triazoleand thiadiazole.

Examples of unsaturated monocyclic heterocyclic groups includeunsaturated derivatives of the aromatic and saturated monocyclicheterocycles mentioned above.

Examples of unsaturated 7-membered heterocycles includetrithiatriazepines and trithiadiazepines. Examples of saturated 5- to7-membered monocyclic heterocycles especially include tetrahydrofuran,dioxolane, imidazolidine, pyrazolidine, piperidine, dioxane, morpholine,dithiane, thiomorpholine, piperazine, trithiane, oxepine and azepine.

Examples of aromatic bicyclic heterocyclic groups in which eachmonocycle is 5- to 7-membered include indolizine, indole, isoindole,benzofuran, benzopyran, benzothiophene, indazole, benzimidazole,benzothiazole, benzofurazane, benzothiofurazane, purine, quinoline,isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline,naphthyridines, pyrazolotriazine (such as pyrazolo-1,3,4-triazine),pyrazolopyrimidine and pteridine.

The saturated and unsaturated derivatives of these groups are examplesof saturated and, respectively, unsaturated bicyclic heterocyclicgroups.

Examples of aromatic tricyclic heterocyclic groups include thoseconsisting of 5- to 7-membered monocycles, such as acridine or lecarbazole. The saturated and unsaturated derivatives of these groups areexamples of saturated and, respectively, unsaturated tricyclicheterocyclic groups.

The aromatic carbocyclic radicals are preferably C₆-C₁₈.

Among these radicals that may especially be mentioned are phenyl,naphthyl, anthryl and phenanthryl radicals.

The arylene radicals are divalent radicals derived from thecorresponding C₆-C₁₈ aryl groups by replacement of a hydrogen atom witha bond. Phenylene is the preferred arylene group.

Saturated carbocyclic radicals are especially cycloalkyl radicals,preferably C₃-C₁₈ and better still C₃-C₁₀ cycloalkyl radicals, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, adamantyl or norbornyl.

The unsaturated carbocyclic groups comprise one or more, preferably 1 to3, ethylenic double bonds and generally consist of from 6 to 18 andbetter still from 6 to 10 carbon atoms. Examples of these arecycloalkenyl radicals, and especially cyclohexenyl radicals.

Some of the compounds of the invention bear a double bond between thecarbon CR¹R² and the carbon CR³R⁴ alpha to CR¹R². Thus, if n=1, thecompounds in question have the formula:

If n=2, the compounds in question have the formula:

If either R¹ or R² forms with either R³ or R⁴ a saturatedhydrocarbon-based chain, it is preferred for the groups R¹ (or R²) andR³ (or R⁴) to be on two adjacent carbons. The resulting compound has,for example, the formula:

If L is an optionally substituted saturated or unsaturated aliphatichydrocarbon-based chain, interrupted by optionally substituted arylene,L may represent:

-   -   -aa-AA-    -   -AA-aa-    -   -aa₁-AA-aa₂-; or    -   -AA₁-aa-AA₂

in which aa, aa₁ and aa₂ independently represent an optionallysubstituted, saturated or unsaturated hydrocarbon-based chain; AA, AA₁and AA₂ independently represent optionally substituted arylene.

Preferably, R¹, R², R³ and R⁴ represent H or alkyl, for example methyl.

Advantageously, n represents 1 or 2.

Preferred meanings of R⁷ are H and alkyl, preferably ethyl or methyl.

Preferably, L represents alkylene, alkenylene or -alk°-Ar°-, in whichalk° represents alkylene and Ar° represents phenylene, such as:

A preferred subgroup of compounds of the invention consists of thecompounds for which L represents C₁-C₄ alkylene, such as propylene ormethylene; aa₃-C(CH₃)₂—, in which -aa₃- represents nothing oralternatively represents a C₁-C₄ alkylene radical;

-aa₄-C(CH₃)(C₂H₅)—, in which -aa₄ is as defined for -aa₃-;

Advantageously, Z represents alkyl optionally substituted by one or moreradicals T; alkenyl optionally substituted by one or more radicals T;alkynyl optionally substituted by one or more radicals T; phenyloptionally substituted by one or more radicals T; cycloalkyl optionallysubstituted by one or more radicals T; monocyclic or bicyclic heteroaryloptionally substituted by one or more radicals T; -alk¹-Cy¹-, in whichalk¹ represents alkylene, preferably —CH₂— and Cy¹ represents phenyloptionally substituted by one or more radicals T, or alternatively Cy¹represents cycloalkyl, optionally substituted by one or more radicals T;T representing cyano, optionally halogenated alkyl, such asperhaloalkyl, optionally halogenated alkoxy or a halogen atom.

A preferred subgroup of compounds consists of the compounds definedabove for which Z represents alkyl optionally substituted by cyano;phenyl optionally substituted by optionally halogenated alkyl (such astrifluoromethyl) or with optionally halogenated alkoxy; phenylalkyl, inwhich phenyl is substituted by one or more halogen atoms, alkyl oralkoxy; optionally halogenated monocyclic or bicyclic heteroaryl (suchas trifluoromethyl) or with optionally halogenated alkoxy; alkynyl; orcycloalkylalkyl.

In a more particularly preferred manner, Z represents C₁-C₁₂ alkyl;C₂-C₁₃ cyanoalkyl; phenyl substituted by one or more halogen(s),optionally halogenated alkyl, or alkoxy; heteroaryl substituted by oneor more halogen(s), optionally halogenated alkyl, or alkoxy; benzyl orphenethyl optionally substituted by one or more halogen, alkyl oralkoxy; norbornyl; —(CH₂)_(m)—C═C—P°, in which m is an integer between 0and 3 and P° represents C₁-C₆ alkyl; cyclohexylmethyl.

Another subgroup of preferred compounds is the group consisting of thecompounds of the formula I in which n=1; R¹, R², R³ and R⁴ represent ahydrogen atom; Y represents O; R⁵ represents (C₁-C₁₀)alkyl;(C₂-C₁₀)alkynyl; -alk¹-Cy¹, in which alk¹ represents (C₁-C₃)alkylene andCy¹ represents phenyl optionally substituted by one or more radicals T,in which T is as defined above; R⁶ represents W, in which X represents Oor NH; and L represents (C₁-C₃)alkylene.

Among these compounds, the following are especially preferred:

→those for which X represents NH; and R⁵ represents (C₁-C₁₀) alkyl;

→those for which X represents O; R⁵ represents (C₁-C₁₀)alkyl;(C₂-C₁₀)alkynyl; or -alk¹-Cy¹, in which alk¹ represents (C₁-C₃) alkyleneand Cy¹ represents phenyl.

Table α below collates 12 preferred subgroups of the invention accordingto the values of n and of Y. TABLE α n Y 1 2 3 O 1 2 3 —N—OH 4 5 6—N—O-alkyl 7 8 9 CR¹⁰R¹¹ 10  11  12 

Table β below moreover defines the preferred subgroups 13 to 40 of theinvention according to the values of X and of R⁷ if, in formula I, Wrepresents —X-L-CO₂R⁷. TABLE β X N-carbocyclic R⁷ O NH N-alkyl NCR′NSO₂R′ group —S(O)_(m) H 13 14 15 16 17 18 19 hydrocarbon-based 20 21 2223 24 25 26 aliphatic carbocyclic 27 28 29 30 31 32 33 heterocyclic 3435 36 37 38 39 40

Table γ collates the preferred subgroups 41 to 47 of compounds of theformula I for which W represents —X-L-Tet, according to the values of X.TABLE γ N-carbocyclic X O NH N-alkyl NCOR′ NSO₂R′ group —S(O)_(m)Preferred sub- 41 42 43 44 45 46 47 group No

Matrix δ below moreover defines preferred subgroups derived from thesubgroups 1 to 47 defined above. More specifically, the elements of thismatrix, which each represent preferred subgroups of the invention, aredefined in the form of a couple, each member of the couple indicatingthe origin of the subgroup and thereby defining n, Y and W.$\begin{matrix}\delta \\\quad \\\quad \\\quad \\\quad \\\quad \\\quad \\\quad \\\quad \\\quad \\\quad \\\quad\end{matrix}\begin{pmatrix}\left( {1,13} \right) & \left( {1,14} \right) & \cdots & \left( {1,i} \right) & \cdots & \left( {1,47} \right) \\\left( {2,13} \right) & \left( {2,14} \right) & \cdots & \left( {2,i} \right) & \cdots & \left( {2,47} \right) \\\left( {3,13} \right) & \left( {3,14} \right) & \cdots & \left( {3,i} \right) & \cdots & \left( {3,47} \right) \\\left( {4,13} \right) & \left( {4,14} \right) & \cdots & \left( {4,i} \right) & \cdots & \left( {4,47} \right) \\\left( {5,13} \right) & \left( {5,14} \right) & \cdots & \left( {5,i} \right) & \cdots & \left( {5,47} \right) \\\left( {6,13} \right) & \left( {6,14} \right) & \cdots & \left( {6,i} \right) & \cdots & \left( {6,47} \right) \\\left( {7,13} \right) & \left( {7,14} \right) & \cdots & \left( {7,i} \right) & \cdots & \left( {7,47} \right) \\\left( {8,13} \right) & \left( {8,14} \right) & \cdots & \left( {8,i} \right) & \cdots & \left( {8,47} \right) \\\left( {9,13} \right) & \left( {9,14} \right) & \cdots & \left( {9,i} \right) & \cdots & \left( {9,47} \right) \\\left( {10,13} \right) & \left( {10,14} \right) & \cdots & \left( {10,i} \right) & \cdots & \left( {10,47} \right) \\\left( {11,13} \right) & \left( {11,14} \right) & \cdots & \left( {11,i} \right) & \cdots & \left( {11,47} \right) \\\left( {12,13} \right) & \left( {12,14} \right) & \cdots & \left( {12,i} \right) & \cdots & \left( {12,47} \right)\end{pmatrix}$

in which i represents one of the subgroups 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 43, 44, 45, 46, 46 and 47 defined in Tables β and γ.

The matrix ε defined below also collates additional subgroups derivedfrom the subgroups (1,13) 2 (12,47) defined in matrix δ et and alsocharacterised by the meaning taken by Z. These subgroups are designatedby the trinomials (l, i, k), in which (l, i) defines the subgroup fromwhich is derived the subgroup (l, i, k), (l, i) being a subgroup of thematrix δ and k, which represents a, b or c, defines the meaning taken byZ in the subgroup (l, i, k), it being understood that:

-   -   a represents a saturated or unsaturated aliphatic        hydrocarbon-based group;    -   b represents an optionally substituted, saturated, unsaturated        and/or aromatic carbocyclic or heterocyclic radical; and    -   c represents alk-Cy, in which alk and Cy are as defined above.        $\begin{matrix}        \quad \\        \quad \\        \quad \\        ɛ \\        \quad \\        \quad \\        \quad \\        \quad \\        \quad \\        \quad \\        \quad \\        \quad        \end{matrix}\begin{pmatrix}        \begin{pmatrix}        {1,13,a} \\        {1,13,b} \\        {1,13,c}        \end{pmatrix} & \begin{pmatrix}        {1,14,a} \\        {1,14,b} \\        {1,14,c}        \end{pmatrix} & \cdots & \begin{pmatrix}        {1,i,a} \\        {1,i,b} \\        {1,i,c}        \end{pmatrix} & \cdots & \begin{pmatrix}        {1,47,a} \\        {1,47,b} \\        {1,47,c}        \end{pmatrix} \\        \begin{pmatrix}        {2,13,a} \\        {2,13,b} \\        {2,13,c}        \end{pmatrix} & \begin{pmatrix}        {2,14,a} \\        {2,14,b} \\        {2,14,c}        \end{pmatrix} & \cdots & \begin{pmatrix}        {2,i,a} \\        {2,i,b} \\        {2,i,c}        \end{pmatrix} & \cdots & \begin{pmatrix}        {2,47,a} \\        {2,47,b} \\        {2,47,c}        \end{pmatrix} \\        \begin{pmatrix}        {3,13,a} \\        {3,13,b} \\        {3,13,c}        \end{pmatrix} & \begin{pmatrix}        {3,14,a} \\        {3,14,b} \\        {3,14,c}        \end{pmatrix} & \cdots & \begin{pmatrix}        {3,i,a} \\        {3,i,b} \\        {3,{i;c}}        \end{pmatrix} & \cdots & \begin{pmatrix}        {3,47,a} \\        {3,47,b} \\        {3,47,c}        \end{pmatrix} \\        \begin{pmatrix}        {4,13,a} \\        {4,13,b} \\        {4,13,c}        \end{pmatrix} & \begin{pmatrix}        {4,14,a} \\        {4,14,b} \\        {4,14,c}        \end{pmatrix} & \cdots & \begin{pmatrix}        {4,i,a} \\        {4,i,b} \\        {4,i,c}        \end{pmatrix} & \cdots & \begin{pmatrix}        {4,47,a} \\        {4,47,b} \\        {4,47,c}        \end{pmatrix} \\        \begin{pmatrix}        {5,13,a} \\        {5,13,b} \\        {5,13,c}        \end{pmatrix} & \begin{pmatrix}        {5,14,a} \\        {5,14,b} \\        {5,14,c}        \end{pmatrix} & \cdots & \begin{pmatrix}        {5,i,a} \\        {5,i,b} \\        {5,i,c}        \end{pmatrix} & \cdots & \begin{pmatrix}        {5,47,a} \\        {5,47,b} \\        {5,47,c}        \end{pmatrix} \\        \begin{pmatrix}        {6,13,a} \\        {6,13,b} \\        {6,13,c}        \end{pmatrix} & \begin{pmatrix}        {6,14,a} \\        {6,14,b} \\        {6,14,c}        \end{pmatrix} & \cdots & \begin{pmatrix}        {6,i,a} \\        {6,i,b} \\        {6,i,c}        \end{pmatrix} & \cdots & \begin{pmatrix}        {6,47,a} \\        {6,47,b} \\        {6,47,c}        \end{pmatrix} \\        \begin{pmatrix}        {7,13,a} \\        {7,13,b} \\        {7,13,c}        \end{pmatrix} & \begin{pmatrix}        {7,14,a} \\        {7,14,b} \\        {7,14,c}        \end{pmatrix} & \cdots & \begin{pmatrix}        {7,i,a} \\        {7,i,b} \\        {7,i,c}        \end{pmatrix} & \cdots & \begin{pmatrix}        {7,47,a} \\        {7,47,b} \\        {7,47,c}        \end{pmatrix} \\        \begin{pmatrix}        {8,13,a} \\        {8,13,b} \\        {8,13,c}        \end{pmatrix} & \begin{pmatrix}        {8,14,a} \\        {8,14,b} \\        {8,14,c}        \end{pmatrix} & \cdots & \begin{pmatrix}        {8,i,a} \\        {8,i,b} \\        {8,i,c}        \end{pmatrix} & \cdots & \begin{pmatrix}        {8,47,a} \\        {8,47,b} \\        {8,47,c}        \end{pmatrix} \\        \begin{pmatrix}        {9,13,a} \\        {9,13,b} \\        {9,13,c}        \end{pmatrix} & \begin{pmatrix}        {9,14,a} \\        {9,14,b} \\        {9,14,c}        \end{pmatrix} & \cdots & \begin{pmatrix}        {9,i,a} \\        {9,i,b} \\        {9,i,c}        \end{pmatrix} & \cdots & \begin{pmatrix}        {9,47,a} \\        {9,47,b} \\        {9,47,c}        \end{pmatrix} \\        \begin{pmatrix}        {10,13,a} \\        {10,13,b} \\        {10,13,c}        \end{pmatrix} & \begin{pmatrix}        {10,14,a} \\        {10,14,b} \\        {10,14,c}        \end{pmatrix} & \cdots & \begin{pmatrix}        {10,i,a} \\        {10,i,b} \\        {10,i,c}        \end{pmatrix} & \cdots & \begin{pmatrix}        {10,47,a} \\        {10,47,b} \\        {10,47,c}        \end{pmatrix} \\        \begin{pmatrix}        {11,13,a} \\        {11,13,b} \\        {11,13,c}        \end{pmatrix} & \begin{pmatrix}        {11,14,a} \\        {11,14,b} \\        {11,14,c}        \end{pmatrix} & \cdots & \begin{pmatrix}        {11,i,a} \\        {11,i,b} \\        {11,i,c}        \end{pmatrix} & \cdots & \begin{pmatrix}        {11,47,a} \\        {11,47,b} \\        {11,47,c}        \end{pmatrix} \\        \begin{pmatrix}        {12,13,a} \\        {12,13,b} \\        {12,13,c}        \end{pmatrix} & \begin{pmatrix}        {12,14,a} \\        {12,14,b} \\        {12,14,c}        \end{pmatrix} & \cdots & \begin{pmatrix}        {12,i,a} \\        {12,i,b} \\        {12,i,c}        \end{pmatrix} & \cdots & \begin{pmatrix}        {12,47,a} \\        {12,47,b} \\        {12,47,c}        \end{pmatrix}        \end{pmatrix}$

it being understood that i is as defined above.

Among the preferred subgroups of the matrix ε, a distinction is madebetween the compounds for which R⁵═W and those for which R⁶═W.

The compounds of the formula I can be prepared by performing a processcomprising the reaction of a compound of the formula II:

in which

R¹, R², R³, R⁴, n and Y are as defined above for formula I, G represents—XH, in which X is S or O; NHCOCF₃ or NHR⁸, R⁸ being as defined abovefor formula I, and Z° is a radical that is a precursor of Z, oralternatively Z° represents Z, Z being as defined above for formula I,Z° and G being in positions 2 and 3 of the phenyl nucleus;

with a compound of the formula III:Gp-L-CO₂R⁷  IIIin which R⁷ and L are as defined above for formula I and Gp represents aleaving group, in the presence of a base.

The expression “Z° and G are in position 2 or 3 of the phenyl nucleus”means that either Z° or G is in position 2 and the other is in position3. More generally, if two substituents are in positions 2 and 3, thismeans that one of the substituents is in position 2 and the other inposition 3.

The reaction of II with III leads to the formation of a compound of theformula IV:

Gp may represent, for example, a halogen atom, preferably bromine, anoptionally halogenated alkylsulfonyloxy group or an arylsulfonyloxygroup optionally substituted by alkyl (such as mesyloxy, CF₃—SO₂—O— orp-tolylsulfonyloxy).

If Z° represents a precursor of Z, in formula II, it is preferably ahalogen atom, such as I or Br or an —OSO₂CF₃ group.

Examples of bases include mineral bases, such as K₂CO₃, Na₂CO₃, KHCO₃,NaHCO₃ or Cs₂CO₃ or alternatively an organic base, such as an alkalimetal alkoxide, such as sodium or potassium ethoxide, or sodium orpotassium methoxide.

A stoichiometric amount of base (relative to the amount of compound III)is generally sufficient.

If R⁷ is other than a hydrogen atom, the molar ratio of the base tocompound III preferably ranges between 1 and 5 and better still between1 and 3, for example between 1 and 2.

If R⁷ is a hydrogen atom, the process may be performed in the presenceof a large excess of base.

The reaction solvent is preferably a polar, water-miscible solvent, suchas acetone or a lower C₁-C₄ alkanol, for example ethanol, ordimethylformamide.

The reaction temperature is preferably maintained between 35° C. and150° C., for example between 40 and 100° C.

The molar ratio of the compound of the formula III to the compound ofthe formula II ranges between 1 and 20 equivalents and preferablybetween 1 and 5 equivalents.

The compounds of the formula I in which Z represents Cy, in which Cydenotes an aryl or heteroaryl group can be obtained by reacting thecompounds of the formula IV in which Z° represents Hal, of the formulaIVa:

in which D represents —NHCOCF₃ or —X-L-CO₂R⁷, and L, R⁷, Y, X, R¹, R²,R³, R⁴ and n are as defined for formula I, and Hal represents a halogenatom, such as Br or I, -Hal and D being in position 2 or 3 of the phenylnucleus, with an arylboronic or heteroarylboronic acid of the formula V:Cy B(OH)₂  (V)in which the group Cy optionally bears one or more substituents, forexample one or more substituents T as defined above, in the presence ofa palladium 0 complex and a mineral or organic base.

If D represents —NHCOCF₃, the product resulting directly from thisreaction has the formula IIa:

in which R¹, R², R³, R⁴, n and the group Cy are as defined above, andmust be converted into a compound of the formula I, for example byperforming the process described above.

A palladium 0 complex that will be used more particularly istetrakis(triphenylphosphine)palladium.

Examples of mineral bases that will be mentioned include Na₂CO₃, K₂CO₃,NaHCO₃, KHCO₃, NaOH and KOH.

Examples of organic bases that may be mentioned include alkali metalalkoxides, such as sodium methoxide or ethoxide.

The reaction is preferably performed in an aromatic hydrocarbon, such astoluene, a xylene or benzene; an aliphatic hydrocarbon, such as heptaneor hexane; a halogenated aromatic hydrocarbon; a C₁-C₄ lower alcohol,such as ethanol or methanol; a cyclic ether, such as tetrahydrofuran; oran amide, such as dimethylformamide.

The reaction temperature is advantageously maintained between 80 and150° C., for example between 90 and 120° C.

According to one preferred embodiment of the invention, the molar ratioof compound V to compound IVa is between 1 and 20 and preferably between1 and 15.

A catalytic amount of the palladium 0 complex is usually sufficient. Byway of example, the molar ratio of compound IVa to the palladium complexranges between 10 and 1000.

The base is present in the reaction medium in a proportion of from 1 to5 equivalents and preferably 2 to 4 equivalents relative to the amountof starting compound IVa.

The compounds of the formula I in which Z represents —CH₂-π, in which πrepresents alkyl, alkenyl, alkynyl or Cy¹, Cy¹ being as defined abovefor Cy in formula I, or alternatively -alk²-Cy¹, alk² representingalkylene and Cy¹ being as defined above, can be obtained by reacting acompound of the formula IVa as defined above with a compound of theformula VII(π-CH₂—)ZnBr or (π-CH₂)ZnCl  VII

in which π is as defined above, in the presence of a palladium complex,such as bis(triphenylphosphine)dichloropalladium.

The reaction is advantageously performed in a polar aprotic solvent, forinstance dimethylformamide.

Preferably, the molar ratio of compound VII to compound IVa rangesbetween 1 and 5 and preferably between 1 and 4.

The reaction temperature is preferably between 15 and 50° C.

The reaction solvent is preferably a polar aprotic solvent, such asdimethylformamide (DMF); an ether, such as dioxane, tetrahydrofuran(THF), diethyl ether or dimethoxyethane; or a mixture thereof, a DMF/THFmixture being preferred.

The palladium complex is used in catalytic amount, preferably in aproportion of from 0.01 to 0.1 equivalent relative to the amount ofcompound VII used.

The compounds of the formula I in which Y represents N—OH can beprepared from the corresponding compounds of the formula I in which Yrepresents O, via the action of hydroxylamine.

Conventionally, a compound of the formula VIII:

in which R¹, R², R³, R⁴, R⁵, R⁶ and n are as defined above for formulaI, is reacted with a hydroxylamine salt in the presence of an alkalimetal salt.

The reaction temperature is preferably between 50 and 120° C., forexample between 70 and 90° C.

A hydroxylamine salt that may be mentioned is the hydrochloride or thehydrobromide.

An alkali metal salt that may be mentioned is sodium acetate.

Usually, the molar ratio of the hydroxylamine salt to the compound ofthe formula VIII ranges between 1 and 3 and better still between 1 and2.

The amount of sodium acetate preferably ranges between 1 and 5 molarequivalents and better still between 2 and 3 molar equivalents relativeto the amount of compound VIII used.

The solvent that can be used is, for example, a C₁-C₄ lower alkanol,such as ethanol.

The compounds of the formula I in which Y represents CR¹⁰R¹¹, in whichR¹⁰ and R¹¹ are as defined above can be prepared from the correspondingcompounds of the formula I in which Y represents O.

To do this, a compound of the formula VIII:

in which R¹, R², R³, R⁴, n, R⁵ and R⁶ are as defined above, is reactedwith a compound of the formula IX:(C₆H₅)₃P⁺CR¹⁰R¹¹H, Br⁻  IXin which R¹⁰ and R¹¹ are as defined above, in the presence of a base.

According to one preferred embodiment, the base is an alkali metalhydride, such as NaH.

This reaction is advantageously performed in a polar aprotic solvent,such as an ether, for instance tetrahydrofuran, dioxane or a diethylether; dimethyl sulfoxide; or an amide, such as acetamide ordimethylformamide. Preferably, the solvent is a mixture oftetrahydrofuran and dimethyl sulfoxide.

The reaction temperature ranges between −10 and +15° C., for examplebetween 0 and 10° C.

The molar ratio of compound IX to compound VIII is preferably between 1and 5, for example between 1 and 3 and preferably between 1 and 2.

The compounds of the formula I in which R⁷ represents H are readilyobtained from corresponding compounds of the formula I in which R⁷represents alkyl.

This reaction can be performed by saponification of a compound of theformula I in which R⁷ represents alkyl, preferably methyl or ethyl,using a strong mineral base, such as NaOH or KOH.

This reaction is preferably performed in a water-miscible solvent, forexample a C₁-C₄ lower alkanol, such as methanol or ethanol, as a mixturewith water.

The base is preferably used in a proportion of from 1 to 5 equivalentsrelative to the amount of the ester of the formula I used.

For the preparation of compounds of the formula I in which R¹ and/or R²represents alkyl, the corresponding compound of the formula I in whichR¹ and R² represent H can be reacted, in, a known manner, with analkylating agent.

An example of an alkylating agent that can be used is an alkyl iodide,such as methyl iodide, while at the same time working in the presence ofa hydride, such as sodium hydride.

The solvent is preferably a polar aprotic solvent, such asdimethylformamide.

By way of illustration, the molar ratio of the alkyl iodide to thestarting compound of the formula I in which R¹ and R² are a hydrogenatom ranges between 1 and 10 and preferably between 3 and 8.

The amount of base that needs to be used preferably ranges between 1 and5 equivalents relative to the starting compound of the formula I.

This base is advantageously an alkali metal hydride, such as sodiumhydride.

This reaction is usually performed at a temperature of between 0° and100° C., for example between 20 and 60° C.

This alkylation step can be performed in a similar manner starting withan intermediate compound, during the synthesis of the compound of theformula I.

The compounds of the formula I in which Z represents a saturatedaliphatic hydrocarbon-based radical can be obtained from thecorresponding compounds of the formula I in which Z represents anunsaturated aliphatic hydrocarbon-based radical, by simple catalytichydrogenation under a hydrogen atmosphere in the presence of a catalyst,such as palladium-on-charcoal.

By way of example, a compound of the formula I in which Z is analiphatic hydrocarbon-based radical comprising a triple bond or a doublebond can be converted via catalytic hydrogenation into the correspondingcompound of the formula I in which Z is a saturated hydrocarbon-basedradical.

Typical reaction conditions are:

-   -   an H₂ pressure of from 1.5 to 5 bar;    -   a catalyst: 5 to 10% palladium-on-charcoal;    -   a solvent, such as a C₁-C₄ lower alkanol, for instance ethanol;    -   a reaction temperature of between 15 and 60° C.

The compounds of the formula II:

in which R¹, R², R³, R⁴, Z°, n and G are as defined above, Y representsO and n represents 1, can be prepared by cyclisation of thecorresponding compounds of the formula X:

in which Z° and G are as defined above, in the presence of an acid, at atemperature of between 40 and 180°, or even between 50 and 150° C.,preferably between 70 and 130° C.

A suitable acid is polyphosphoric acid.

The molar amount of polyphosphoric to compound X preferably rangesbetween 4 and 50 equivalents.

The reaction is advantageously performed in a solvent, such as anoptionally halogenated aliphatic hydrocarbon, such as hexane, heptane,dichloromethane, tetrachloromethane or chloroform, or an optionallyhalogenated aromatic hydrocarbon, such as toluene, benzene, xylene or achlorobenzene.

The compounds of the formula II in which R¹, R², R³, R⁴ and Z° are asdefined above, and G represents methoxy, Y represents O and n representsI can be prepared by cyclisation of a compound of the formula X in whichG represents —O—CH₃, under the same conditions as described above forthe cyclisation of compound X.

The compounds of the formula II:

in which R¹, R², R³, R⁴, n, Z° and G are as defined above and Yrepresents O and n=1, can be obtained by cyclisation of a correspondingcompound of the formula XI:

in which hal is a halogen atom, and Z° and G are as defined above, inthe presence of a Lewis acid, such as AlCl₃ or a mineral acid.

The reaction is usually performed at a temperature of between 15° C. and100° C.

Preferably, the molar ratio of AlCl₃ to the compound of the formula XIranges between 1 and 5 and better still between 2 and 4.

The solvent is preferably a halogenated aliphatic hydrocarbon, such asdichloromethane.

The compound of the formula XI can be simply prepared from thecorresponding acid of the formula X via the action of SOCl₂. Thisreaction is usually performed at a temperature of between 40 and 80° C.

According to one preferred embodiment, the solvent is a halogenatedaliphatic hydrocarbon as defined above.

This same cyclisation reaction can be performed using a compound of theformula XI in which G represents —OCH₃. In this case, it leads to thecorresponding compound of the formula II in which G represents —OCH₃.

The compounds of the formula X are commercially available or preparedsimply by carrying out conventional processes using commerciallyavailable products.

The compounds XII of the general formula II in which Z°, in position 2,represents I and G, in position 3, represents —OH, can be obtained fromthe corresponding compounds of the formula XIII by carrying out reactionscheme 1.

In step i), a compound of the formula XIII is reacted with ICl in aceticacid medium.

Preferably, the amount of ICl ranges between 1 and 3 equivalents andpreferably between 1 and 2 equivalents.

The reaction temperature is between 50 and 120° C., for example between80 and 100° C.

In step ii), cyclisation of the compound of the formula XIV is carriedout by performing a process similar to the one described in the case ofthe compound of the formula X.

In this case, it is possible to work at a temperature of between 40° C.and 180° C.

In step iii), the compound of the formula XV is treated, at atemperature of between 40° C. and 180° C. and preferably between 60° C.and 140° C., with a Lewis acid, such as AlCl₃. Advantageously, the AlCl₃is used in a proportion of from 1 to 10 equivalents, for example from 1to 5 equivalents, relative to the amount of compound XV present in themedium.

The reaction solvent is preferably an aromatic solvent, such as toluene,benzene or xylene.

The compounds of the formula X in which G, in position 3, represents—OCH₃, can be obtained by performing a process comprising the steps ofreaction scheme 2:

In step iv), bromine is reacted with the compound of the formula XVI.

The reaction solvent is preferably a halogenated aliphatic hydrocarbonchosen from tetrachloromethane, chloroform and dichloromethane.

The reaction temperature is preferably between 15 and 35° C.

The molar ratio of bromine to the compound of the formula XVI usuallyranges between 1 and 1.5.

In step v), the compound obtained of the formula XVII is saponified in aconventional manner, for example via the action of KOH or NaOH, forexample in a mixture of water and of C₁-C₄ lower alkanol.

The compounds of the formula II in which G represents —OH, n represents2, Y represents O and Z° represents 1-alkyl can be obtained byperforming the process illustrated in reaction scheme 3:

in which Q represents 1-alkynyl and M represents alkyl.

In step vi), a 1-alkyne is reacted with the compound of the formula XIXin the presence of a palladium complex, copper iodide and a base.

An example of a palladium complex that will advantageously be used isPdCl₂(PPh₃).

The reaction is preferably performed in a solvent, preferably an ether,such as tetrahydrofuran, dioxane, diethyl ether or dimethoxyethane.

The molar ratio of the 1-alkyne to the compound of the formula XIXpreferably ranges between 1 and 3 and better still between 1 and 2.

Advantageously, the amount of CuI ranges between 0.05 and 2 equivalentsrelative to the amount of compound of the formula XIX.

The base that can be used is either triethylamine,4-dimethylaminopyridine, pyridine, 2,6-di-tert-butylpyridine,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and1,4-diazabicyclo[2.2.2]-octane, or a mineral base, such as K₂CO₃.

In step vii), the compound of the formula XX is reacted with aphosphonium bromide of the formula:Br⁻⁺PPh₃—(CH₂)₂—CO₂H  XXIIIin the presence of a hydride.

The general working conditions are those recommended in the techniquefor Wittig reactions.

This reaction is advantageously performed in an ether/dimethyl sulfoxidemixture. A preferred ether that will be used is tetrahydrofuran.

An example of a hydride that may be mentioned is sodium hydride.

The molar ratio of the bromide XXIII to compound XX is usually between 1and 5, for example between 1 and 3.

In step viii), hydrogenation of compound XXI is performed under the sameconditions as described above, followed by cyclisation via the action ofa sulfonic acid.

In step ix), the compound of the formula XXII is treated with AlCl₃ inan aromatic solvent, such as toluene, under the same conditions asdescribed above for step iii) of reaction scheme 1.

The compound of the formula II in which G represents —SH can be preparedby performing the process illustrated in reaction scheme 4:

in which G″ represents OH; G′ represents —O—SO₂—CF₃.

The compound of the formula XXV is treated with 1 to 5 equivalents andpreferably 1 to 3 equivalents of triflic anhydride in the presence of abase.

A solvent for this reaction that will advantageously be used ispyridine, which also acts as the base.

In step xi), a silanethiol, such as triisopropylsilanethiol is reactedwith the compound of the formula XXVI in the presence of a hydrides suchas sodium hydride and a palladium 0 complex, such as Pd(PPh₃)₄.

An ether, such as tetrahydrofuran, dioxane, diethyl ether ordimethoxyethane will advantageously be used as solvent.

The hydride and the triisopropylsilanethiol are placed in contact at atemperature of between —10° C. and +10° C., and the reaction medium isthen brought to a temperature of between 50 and 150° C. and preferablybetween 70 and 100° C., after addition of compound XXVI.

The amounts of compound XXVI, of hydride and of silanethiol areadvantageously stoichiometric.

The compound obtained is treated with tetrabutylammonium fluoride,preferably in an ether, such as dioxane or tetrahydrofuran, in aconventional manner, this reaction allowing the thiol function to bedeprotected.

The compounds of the formula I in which X represents SO or SO₂ areobtained by oxidation of the corresponding compounds of the formula I inwhich X represents S.

The oxidising agent is, for example, meta-chloroperbenzoic acid, whichis used in the reaction medium in a proportion of from 1 to 5 andpreferably 1 to 3 equivalents.

The solvent is preferably a halogenated aliphatic hydrocarbon, such ascarbon tetrachloride, dichloromethane or chloroform.

The reaction is advantageously performed at a temperature of from −10°C. to +10° C.

As a variant, this oxidation reaction can be performed using a reactionintermediate during the synthesis of the compounds of the formula I.

The compounds of the formula II in which G represents —NH—CO—CF₃ can beprepared from the corresponding compounds of the formula XXVII:

in which R¹, R², R³, R⁴, Y, Z° and n are as defined above, and G°represents —NO₂, by performing a process comprising the steps consistingin:a) reacting the compound of the formula XXVII with iron (0) in thepresence of ammonium chloride;b) and then reacting the resulting compound with trifluoroaceticanhydride in acetic medium.

In step a), the process will preferably be performed in the presence ofan excess of iron (O). The molar ratio of the iron to compound XXVIIranges especially between 2 and 10 equivalents and better still between3 and 7 equivalents.

As regards the amount of ammonium chloride, this preferably rangesbetween 0.1 and 1 equivalent relative to the amount of compound of theformula XXVII.

The reaction temperature is advantageously between 40 and 120° C., forexample between 50 and 90° C.

The solvent preferably consists of a mixture of water and of a C₁-C₄lower alkanol.

By way of illustration, a mixture of water and ethanol will be selected.

In step b), the process is performed in acetic acid as solvent. Themolar ratio of the trifluoroacetic anhydride to the amine obtained afterstep a) advantageously ranges between 1 and 1.5 equivalents.

The reaction temperature advantageously ranges between −10° C. and +10°C., for example between −5 and 0° C.

The compounds of the formula Xa in which G represents —O—CH₃ and Z°represents alkyl can be obtained by performing the process illustratedin reaction scheme 5.

in which ALK and ALK′ independently represent lower alkyl, for exampleC₁-C₄ alkyl.

In step xii), a compound of the formula XXVIII is reacted with an acidchloride of the formula XXXII:Cl—CO—CH₂-ALK′  XXXIIin the presence of a Lewis acid, such as aluminium chloride.

The process is preferably performed in the presence of 1 to 5equivalents of Lewis acid relative to compound XXVIII.

The solvent is preferably chosen from a halogenated aliphatichydrocarbon, such as dichloromethane, chloroform or carbontetrachloride.

The reaction temperature ranges between 25 and 100° C.

The molar ratio between the acid chloride of the formula XXXII and thecompound of the formula XXVIII usually ranges between 1 and 5, forexample between 1 and 3.

In step xiii), reduction of compound XXIX obtained is performed via theaction of a suitable hydride, in a conventional mariner. By way ofexample, an alkali metal borohydride is used, such as sodiumborohydride, and the process is performed in a C₁-C₄ alkanol.

The borohydride and the ketone of the formula XXIX are preferably usedin stoichiometric amounts.

In step xiv), compound XXX is dehydrated via the action of a dehydratingagent, such as p-toluenesulfonic acid, while working in an aromatichydrocarbon, such as toluene. The p-toluenesulfonic acid is used in aproportion of from 0.01 to 1 equivalent.

Next, in step xv), hydrogenation of the double bond is performed via theaction of hydrogen, in the presence of palladium-on-charcoal. Thisreaction is preferably performed under the reaction conditions describedabove.

The resulting compound is then saponified in a conventional manner, instep xv′). To do this, a mineral base chosen from K₂CO₃, Na₂CO₃, NaHCO₃,KHCO₃, KOH and NaOH will preferably be used, and will be reacted withthe ester obtained in the preceding step, the reaction preferably takingplace in a mixture of lower alkanol (preferably a C₁-C₄ alkanol) andwater, such as an ethanol/water or methanol/water mixture. The amount ofbase preferably ranges between 1 and 5 molar equivalents relative to theinitial amount of ester.

The compounds of the formula II in which G represents —XH in which X isO can be prepared from the corresponding compounds of the formulaXXXIII:

in which R¹, R², R³, R⁴, n and Z° are as defined above, by reactingthese compounds with a strong Lewis acid, such as aluminium chloride.

This reaction is performed, for example, in a polar aprotic solvent, forinstance an aromatic hydrocarbon, such as benzene or toluene.

The molar ratio of AlCl₃ to the compound of the formula XXXIIIpreferably ranges between 1 and 5 and preferentially between 2 and 3.

This reaction is advantageously performed at a temperature of between50° and 120° C., for example between 90° and 110° C.

The compounds of the formula XXXIII can be readily prepared byperforming the following reaction scheme:

In step xvi), the compound of the formula XXXIV is reacted with triflicanhydride. This reaction is advantageously performed in a solvent ofpolar aprotic type in the presence of a base, such as a base chosen frompyridine, 4-dimethylaminopyridine, 2,6-di-tert-butylpyridine,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and1,4-diazabicyclo-[2.2.2]octane. If the selected base is pyridine, it mayadvantageously be used as solvent.

The molar ratio of the triflic anhydride to the compound of the formulaXXXIV advantageously ranges between 1 and 2 equivalents.

The reaction is preferably performed at a temperature of between −10°and +15°, for example between −5° and +5° C.

In step xvii), compound XXXV obtained in the preceding step is reactedwith a compound of the formula XXXVI:Z°-ZnBr  XXXVIin which Z° is as defined above, in the presence of a palladium complex.A palladium complex that may be mentioned isdichlorobis(triphenylphosphine)palladium.

This reaction is preferably performed in a polar aprotic solvent, suchas dimethylformamide, acetamide, dimethylacetamide, formamide orhexamethylphosphorylamide. Usually, a molar ratio of compound XXXVI tocompound XXXV of between 1 and 3 equivalents and preferably between 1and 2 equivalents is used. The reaction temperature will preferably bemaintained between 15° and 50° C. and better still between 20° and 40°C.

The solvent that can be used for this reaction is preferably a polaraprotic solvent, such as an ether, or dimethylformamide. Ethers that maybe mentioned include cyclic ethers, such as dioxane or tetrahydrofuran,or a linear ether, such as diethyl ether, di-tert-butyl ether or aglyme, such as diglyme. The solvent is preferably tetrahydrofuran.

Some of the intermediate compounds described above are novel.

The invention relates to these novel intermediate compounds. Among thepreferred intermediate compounds of the invention, the followingsubgroups will be distinguished:

-   -   1) a compound of the formula II    -   in which:    -   R¹ and R² are chosen independently from a hydrogen atom and a        C₁-C₆ alkyl group, such as methyl; Z° represents 1, Br or a        C₁-C₁₀ alkyl group; and G represents —OH; —SH; —NH₂; —OCH₃;        —NH—CO—CH₃; —NH—CO—CF₃;    -   2) a compound of the formula II chosen from:

-   2,2-dimethyl-5-n-hexyl-6-hydroxyindan-1-one;

-   5-n-hexyl-6-hydroxyindan-1-one;

-   5-n-hexyl-6-mercaptoindan-1-one;

-   5-iodo-6-methoxyindan-1-one;

-   5-bromo-6-aminoindan-1-one;

-   5-bromo-6-hydroxyindan-1-one;

-   2,2-dimethyl-5-n-hexyl-6-methoxyindan-1-one; and

-   5-bromo-6-trifluoromethylcarbonylaminoindan-1-one;    -   3) a compound of the formula IVb²:    -   in which:    -   R¹ and R² are chosen independently from a hydrogen atom and a        C₁-C₅ alkyl group, such as —CH₃; Halo represents a halogen atom,        such as an iodine atom; L and R⁷ are as defined above, it being        understood that Hal° and —O-L-CO₂R⁷ are in position 2 or 3.    -   4) a compound of the formula IVb² in which R¹ and R² are        hydrogen atoms; Halo represents a bromine or iodine atom and is        in position 2; and —O-L-CO₂R⁷ is in position 3;    -   5) a compound of the formula XXVIIa:    -   in which    -   R¹ and R² represent a hydrogen atom or a (C₁-C₆)alkyl group,        such as —CH₃;    -   Z° is as defined above for formula II; and G° represents NO₂;    -   6) 5-bromo-6-nitroindan-1-one;    -   7) a compound of the formula XX:    -   in which Q represents C₂-C₁₀ 1-alkynyl, preferably 1-hexynyl;    -   8) an intermediate compound in the preparation of the compounds        of the formula I, chosen from:

-   5-methoxy-6-trifluoromethylsulfonyloxyindan-1-one;

-   5-methoxy-6-bromoindan-1-one; and

-   5-hydroxy-6-bromoindan-1-one.

According to another of its aspects, the invention relates to apharmaceutical composition comprising at least one compound of theformula I in combination with at least one pharmaceutically acceptableexcipient.

These compositions can be administered orally in the form of tablets,gel capsules or granules with immediate release or controlled release,intravenously in the form of an injectable solution, or transdermally inthe form of a solution, cream or gel.

The compounds are preferably administered in doses from about 1 to 100mg and in particular from about 10 to 200 mg per dosage unit. The dailydose is preferably within the range from 10 to 200 mg/kg of body weight.However, the specific dose for each patient depends on a wide variety offactors, especially including the efficacy of the specific compoundused, the age, the body weight, the general state of health, the sex,the diet, the time and mode of administration, the level of excretion,the combination with other medicaments and the acute nature of theparticular disease targeted by the therapy. Oral administration ispreferred.

A solid composition for oral administration is prepared by adding to theactive principle a filler and, where appropriate, a binder, adisintegrating agent, a lubricant, a colorant or a flavour enhancer, andby forming the mixture into a tablet, a coated tablet, a granule, apowder or a capsule.

Examples of fillers include lactose, corn starch, sucrose, glucose,sorbitol, crystalline cellulose and silicon dioxide, and examples ofbinders include poly(vinyl alcohol), poly(vinyl ether), ethylcellulose,methylcellulose, calcium citrate, shellac, hydroxypropylcellulose,acacia, gum tragacanth, gelatine, hydroxypropylmethylcellulose, calciumcitrate [sic], dextrin and pectin. Examples of lubricants includemagnesium stearate, talc, polyethylene glycol, silica and hardened plantoils. The colorant may be any of those permitted for used inmedicaments. Examples of flavour enhancers include cocoa powder, mint inherb form, aromatic powder, mint in oil form, borneol and cinnamonpowder.

Obviously, the tablet or granule can be suitably coated with sugar,gelatine or the like.

An injectable form comprising the compound of the present invention asactive principle is prepared, where appropriate, by mixing the saidcompound with a pH regulator, a buffer agent, a suspension agent, asolubiliser, a stabiliser, an isotonic agent and/or a preserving agent,and by converting the mixture into a form for intravenous, subcutaneousor intramuscular injection, according to a standard process. Whereappropriate, the injectable form obtained can be freeze-dried via astandard process.

Examples of suspension agents include methylcellulose, polysorbate 80,hydroxyethylcellulose, acacia, powdered gum tragacanth, sodiumcarboxymethylcellulose and polyethoxylated sorbitan monolaurate.

Examples of solubilisers include castor oil solidified withpolyoxyethylene, polysorbate 80, nicotinamide, polyethoxylated sorbitanmonolaurate and the ethyl ester of castor oil fatty acid.

In addition, the stabiliser encompasses sodium sulfite, sodiummetasulfite and ether, while the preserving agent encompasses methylp-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenyl [sic],cresol and chlorocresol.

The invention is also directed towards medicaments comprising at leastone compound of the formula I and/or the pharmaceutically acceptablederivatives, solvates and stereoisomers thereof, and also mixturesthereof in all proportions, and optionally one or more excipients and/oradjuvants.

The compounds of the invention are powerful activators of the PPARα andPPARγ isoforms. As a result of this activity, they have a substantialhypolipidaemiant and hypoglycaemiant effect.

Thus, the invention is also directed towards the use of a compound ofthe formula I and/or the pharmaceutically acceptable derivatives,solvates and stereoisomers thereof, including mixtures thereof in allproportions, for the preparation of a medicament for the treatment of anindividual suffering from a disease or condition mediated by aninsufficiency of activity of the PPARα and PPARγ isoforms in their roleof regulating lipidaemia and glycaemia.

In particular, the invention is directed towards the use of a compoundof the formula I and/or the pharmaceutically acceptable derivatives,solvates and stereoisomers thereof, including mixtures thereof in allproportions, for the preparation of a medicament for the prevention ofor treating dyslipidaemia, atherosclerosis and diabetes.

The measurement of the PPAR activation was performed according to atechnique described by Lehmann et al. (1995, J. Biol. Chem. 270:12953-12956).

CV-1 cells (monkey kidney cells) are co-transfected with an expressionvector for the chimeric proteins PPARα-Gal4 or PPARγ-Gal4 and with a“reporter” plasmid that allows the expression of the luciferase geneplaced under the control of a promoter containing Gal4 responseelements.

The cells are plated into 96-well microplates and co-transfected using acommercial reagent with the reporter plasmid (pG5-tk-pGL3) and theexpression vector for the chimeric protein (PPARα-Gal4 or PPARγ-Gal4).After incubating for 4 hours, whole culture medium (comprising 10%foetal calf serum) is added to the wells. After 24 hours, the medium isremoved and replaced with whole medium comprising the test products (50μM final). The products are left in contact with the cells for 18 hours.The cells are then lysed and the luciferase activity is measured using aluminometer. A PPAR activation factor can then be calculated by means ofthe activation of the expression of the reporter gene induced by theproduct (relative to the control cells that have not received anyproduct).

By way of example, the compound of Example 1, at a concentration of 50μM, activates the chimeric protein PPARα-Gal4 by factor of 18, and thechimeric protein PPARγ-Gal4 by a factor of 39. In the absence of thebinding domain for the PPAR α or γ ligand (vector expressing Gal4alone), the luciferase activity measured in the presence of this productis zero.

The present invention is illustrated below with the aid of the examplesthat follow.

The frequency of the NMR machine used to record the proton spectra inthe examples given below is 300 MHz.

s denotes a singlet; d a doublet; t a triplet; q a quartet; sept. aseptet, and m is a multiplet.

m.p. denotes the melting point.

EXAMPLES Example 1 Step a: ethyl3-(3-hexanoyl-4-methoxyphenyl)propanoate

98 ml (0.7 mol) of hexanoyl chloride are added dropwise to a solution of70 g (0.336 mol) of ethyl 3-(4-methoxyphenyl)propanoate in 280 ml ofdichloromethane. 89 g (0.67 mol) of aluminium chloride are then added insmall amounts, and the mixture is heated for one hour at 50° C. Themixture is poured into cold water and extracted with ether. The organicphase is washed with sodium bicarbonate solution. After drying (Na₂SO₄)and evaporating off the solvents, a yellow liquid is obtained, and thendistilled: Bp_(0.4 mmHg)=160° C. (74 g; 72%);

¹H NMR-CHCl₃-δ(ppm): 0.88 (3H, m); 1.21 (3H, m); 1.30 (4H, m); 1.64 (2H,m); 2.57 (2H, m); 2.92 (4H, m); 3.85 (3H, s); 4.10 (2H, m); 6.85 (1H,m); 7.27 (1H, m); 7.45 (1H, m).

Step b: ethyl 3-[3-(1-hydroxyhexyl)-4-methoxyphenyl)propanoate

NaBH₄ (7.6 g; 0.2 mol) is added in small amounts to 61 g (0.2 mol) ofethyl 3-(3-hexanoyl-4-methoxyphenyl)propanoate, as a solution in 500 mlof ethanol. The mixture is heated for 1 hour at 80° C. After 16 hours atroom temperature, the mixture is concentrated under vacuum and pouredinto saturated sodium chloride solution. The resulting mixture isextracted with ether and the organic phase is dried over sodium sulfate.Evaporation of the solvents gives 58 g of product in a 94% yield.

¹H NMR-CHCl₃-δ (ppm): 0.87 (3H, m); 1.22 (3H, m); 1.28 (4H, m); 1.69(1H, m); 1.73 (3H, m); 2.56 (3H, m); 2.87 (2H, m); 3.81 (3H, s); 4.11(2H, m); 4.80 (1H, broad m); 6.78 (1H, m); 7.03 (1H, m); 7.11 (1H, m).

Step c: ethyl 3-(3-hexyl-1-enylmethoxyphenyl)propanoate

A solution of 58 g (0.188 mol) of ethyl3-[3-(1-hydroxyhexyl)-4-methoxyphenyl)propanoate and 2.8 g (14.7 mmol)of para-toluenesulfonic acid in 500 ml of toluene is heated for 3 hours.The water-toluene azeotrope is removed using Dean-Stark apparatus. Aftercooling, the organic phase is washed with water, separated out bysettling of the phases, and dried (Na₂SO₄). Evaporation under vacuum ofthe solvent gives 54.6 g (100%) of an orange oil.

¹H NMR-CHCl₃-δ (ppm): 0.92 (3H, m); 1.23 (3H, m); 1.40 (4H, m); 2.22(2H, m); 2.58 (2H, m); 2.87 (2H, m); 3.81 (3H, s); 4.12 (2H, m);6.02-6.37 (1H, m); 6.58-6.83 (2H, m); 7.00 (1H, m); 7.11-7.30 (1H, m).

Step d: ethyl 3-(3-hexyl-4-methoxyphenyl)propanoate

54.6 g (0.188 mol) of ethyl 3-(3-hexyl-1-enyl-4-methoxyphenyl)propanoateare hydrogenated with 0.8 g of palladium-on-charcoal in 150 ml ofethanol under pressure (200 bar). After filtration of the catalyst andevaporation of the solvent, 45.7 g of product are collected (83%).

¹H NMR-CHCl₃-δ (ppm): 0.88 (3H, m); 1.24 (3H, m); 1.31 (6H, m); 1.55(2H, m); 2.57 (4H, m); 2.87 (2H, m); 3.78 (3H, s); 4.12 (2H, m); 6.74(1H, m); 6.88-7.04 (2H, m)

Step e: 3-(3-hexyl-4-methoxyphenyl)propanoic acid

A mixture of 45.7 g (0.156 mol) of the compound obtained in step d) and300 ml of ethanol, 13 g (0.232 mol) of potassium hydroxide and 150 ml ofwater is heated for 75 minutes at the reflux point of the solvents. Thesolvents are evaporated off, and the residue is taken up in water andextracted with ether. The aqueous phase is acidified and then extractedwith ether. Concentration of the solvents gives a yellow oil whichcrystallises (36 g; 87%).

¹H NMR-CHCl₃-δ (ppm): 0.88 (3H, m); 1.30 (6H, m); 1.54 (2H, m); 2.56(2H, m); 2.63 (2H, m); 2.87 (2H, m); 3.79 (3H, s); 6.75 (1H, m);6.91-7.04 (2H, m).

Step f: 5-hexyl-6-methoxyindan-1-one

18.5 g (69.9 mmol) of 3-(3-hexyl-4-methoxyphenyl)propanoic aciddissolved in 100 ml of xylene are added to a mixture of 100 g ofpolyphosphoric acid and 100 ml of xylene heated to 80° C. The mixture isthen heated at 135° C. for 1 hour 30 minutes. The mixture is poured intowater and extracted with ethyl acetate. The organic phase is washed withsodium bicarbonate solution. The solvents of the organic phase are dried(Na₂SO₄) and evaporated off, and the residue is purified by flashchromatography (9 g; 52%).

¹H NMR-CHCl₃-δ (ppm): 0.88 (3H, m); 1.31 (6H, m); 1.57 (2H, m); 2.66(4H, m); 3.03 (2H, m); 3.84 (3H, s); 7.13 (1H, s); 7.21 (1H, s).

Step g: 5-hexyl-6-hydroxyindan-1-one

5.6 g (22.7 mmol) of 5-hexyl-6-methoxyindan-1-one, 9.4 g of aluminiumchloride and 125 ml of toluene are refluxed for 15 minutes. The mixtureis poured into water and extracted with ether. The organic phase isdried (Na₂SO₄) and the solvents are evaporated off. The residue ispurified by flash chromatography (4.5 g; 85%).

¹H NMR-CHCl₃-δ (ppm): 0.88 (3H, m); 1.32 (6H, m); 1.65 (2H, m); 2.67(4H, m); 3.03 (2H, m); 5.54 (1H, s); 7.15 (1H, s); 7.21 (1H, s).

Step h: ethyl 4-(6-hexyl-3-oxoindan-5-yloxy)butyrate

3.6 ml of ethyl 4-bromobutyrate dissolved in 15 ml of ethanol are addedto a mixture of sodium ethoxide (1.6 g, 0.0233 mol) and5-hexyl-6-hydroxyindan-1-one (4.5 g, 0.0194 mol) in 45 ml of ethanol.The reaction medium is heated for 5 hours at reflux. The mixture ispoured into water and extracted with ether. The organic phase is dried(Na₂SO₄) and the solvents are evaporated off (5.9 g; 60%).

¹H NMR-CHCl₃-δ (ppm): 0.88 (3H, m); 1.25 (3H, m); 1.31 (6H, m); 1.59(2H, m); 2.13 (2H, m); 2.51 (2H, m); 2.67 (4H, m); 3.02 (2H, m); 4.01(2H, m); 4.14 (2H, m); 7.10 (1H, s); 7.21 (1H, s).

Step i: 4-(6-hexyl-3-oxoindan-5-yloxy)butyric acid

A mixture of 70 ml of ethanol, 2.7 g (0.048 mol) of potassium hydroxide,5.9 g (0.017 mol) of ethyl 4-(6-hexyl-3-oxoindan-5-yloxy)butyrate and 35ml of water is heated for 90 minutes at the reflux point of thesolvents. The solvents are evaporated off and the residue is placed inwater and extracted with ether. The aqueous phase is acidified and thenextracted with ether. Concentration of the solvents gives 3.6 g ofproduct, which is purified by flash chromatography (80/20cyclohexane/ethyl acetate): 1.5 g of crude product. Recrystallisationfrom hexane gives 1.3 g, m.p. 88° C., 24%.

¹H NMR-DMSO-δ(ppm): 0.84 (3H, m); 1.27 (6H, m); 1.53 (2H, m); 1.95 (2H,m); 2.40 (2H, m); 2.60 (4H, m); 2.97 (2H, m); 4.02 (2H, m); 7.02 (1H,s); 7.33 (1H, s); 12.13 (1H, broad s).

Example 2 Ethyl 4-[3-methylene-6-hexylindan-5-yloxy]butyrate

5.4 g (15.3 mmol) of methyltriphenylphosphate [sic] bromide are added toa suspension of 1.75 g (14.9 mmol) of potassium tert-butoxide in 20 mlof tetrahydrofuran. The reaction medium is stirred for 1 hour at 25° C.and then cooled to 0° C. A solution of 4.5 g (12.9 mmol) of ethyl4-(6-hexyl-3-oxoindan-5-yloxy)butyrate is added. The mixture is stirredfor 16 hours at 25° C., poured into water and extracted with ether. Theorganic phase is dried (Na₂SO₄) and concentrated under reduced pressure(oil). Purification by flash chromatography (80/20 heptane/ethylacetate) gives an orange oil (3.5 g; 79%).

¹H NMR-DMSO-δ (ppm): 0.84 (3H, m); 1.16 (3H, m); 1.27 (6H, m); 1.48 (2H,m); 1.98 (2H, m); 2.45 (4H, m); 2.71 (2H, m); 2.78 (2H, m); 3.99 (2H,m); 4.06 (2H, m); 4.93 (1H, m); 5.42 (1H, m); 7.01 (1H, s); 7.04 (1H,s).

Example 12 4-(3-methylene-6-hexylindan-5-yloxy)butyric acid

A mixture of 20 ml of ethanol, 0.975 mg (155 mmol) of potassiumhydroxide, 1.2 g (35 mmol) of ethyl4-(3-methylene-6-hexylindan-5-yloxy)butyrate and 10 ml of water isheated for 5 hours at the reflux point of the solvents. The ethanol isevaporated off, the residue is taken up in water and the impurities areextracted with ether. The aqueous phase is acidified and then extractedwith ether. Concentration of the solvents gives 1.1 g of product, whichis purified by flash chromatography (50/50 heptane/ethyl acetate) togive a solid m.p.: 90° C. (0.8 g; 72%).

¹H NMR-DMSO-δ (ppm): 0.87 (3H, m); 1.31 (6H, m); 1.57 (2H, m); 2.12 (2H,m); 2.16 (2H, m); 2.63 (4H, m); 3.22 (2H, m); 4.07 (2H, m); 6.14 (1H,m); 6.80 (1H, m); 7.19 (1H, s); 7.26 (1H, s).

Example 18 Step a: 5-hexyl-6-methoxy-2,2-dimethylindan-1-one

5 g (0.02 mol) of 5-hexyl-6-methoxyindan-1-one dissolved in 20 ml ofdimethylformamide are added dropwise to a suspension of 1.8 g (0.04 mol)of sodium hydride in 20 ml of dimethylformamide at 25° C. The mixture isstirred for 15 minutes at this temperature, and 11.4 g (0.1 mol) ofmethyl iodide are then added, while maintaining the temperature below30° C. The reaction medium is stirred for 16 hours at 25° C. A further0.9 g (0.0375 mol) of sodium hydride is added, and 15 minutes later 11.4g (0.1 mol) of methyl iodide are added and the mixture is stirred for 2hours at 25° C. The mixture is then heated for 1 hour at 50° C. It ispoured into water and extracted with ether. The organic phase is dried(Na₂SO₄) and then evaporated under reduced pressure. The orange oilobtained is purified by flash chromatography (dichloromethane, 3.54 g;65%).

¹H NMR-CHCl₃-δ (ppm): 0.97 (3H, m); 1.30 (6H, s); 1.41 (6H, m); 1.67(2H, m); 2.74 (2H, m); 2.98 (2H, s); 3.93 (3H, s); 7.22 (1H, s); 7.34(1H, s).

Step b: 5-hexyl-6-hydroxy-2,2-dimethylindan-1-one

1.93 g (7 mmol) of 5-hexyl-6-methoxy-2,2-dimethylindan-1-one, 2.84 g (21mmol) of aluminium chloride and 40 ml of toluene are heated for 15minutes at reflux. The mixture is poured into water and extracted withether. The organic phase is dried (Na₂SO₄) and the solvent evaporatedoff. The residue is purified by flash chromatography (dichloromethane,2.8 g; 90%).

¹H NMR-CHCl₃-δ (ppm): 0.88 (3H, m); 1.21 (6H, s); 1.33 (6H, m); 1.64(2H, m); 2.67 (2H, m); 2.88 (2H, s); 5.73 (1H, broad s); 7.16 (1H, s);7.19 (1H, s).

Step c: ethyl 4-(6-hexyl-2,2-dimethyl-3-oxoindan-5-yloxy)butyrate

A mixture of 1.3 g (5 mmol) of5-hexyl-6-hydroxy-2,2-dimethylindan-1-one, 40 ml of acetone and 2.5 g(7.5 mmol) of caesium carbonate is heated for 30 minutes at 56° C. 1.46g (7.5 mmol) of ethyl 4-bromobutyrate are added dropwise, and themixture is then heated at reflux for 7 hours.

The resulting mixture is poured onto 1 N hydrochloric acid solution andextracted with ether. The organic phase is dried (Na₂SO₄) and thesolvents are evaporated off: brown oil (2 g; 100%).

¹H NMR-CHCl₃-δ(ppm): 0.88 (3H, m); 1.20 (6H, s); 1.25 (3H, m); 1.32 (6H,m); 1.58 (2H, m); 2.13 (2H, m); 2.51 (2H, m); 2.64 (2H, m); 2.87 (2H,s); 4.02 (2H, m); 4.14 (2H, m); 7.09 (1H, s); 7.15 (1H, s).

Example 19 4-(6-hexyl-2,2-dimethyl-3-oxoindan-5-yloxy)butyric acid

A mixture of 60 ml of ethanol, 0.4 g (7.2 mmol) of potassium hydroxide,1.8 g (4.8 mmol) of ethyl4-(6-hexyl-2,2-dimethyl-3-oxoindan-5-yloxy)butyrate and 20 ml of wateris heated for 2 hours at the reflux point of the solvents. The solventsare evaporated off and the residue is placed in water and extracted withether. The aqueous phase is acidified and then extracted with ether.Concentration of the solvents gives 1.46 g of product, which is purifiedby flash chromatography (95/5 dichloromethane/methanol): 1.18 g; m.p.:82° C.; 71%.

¹H NMR-CHCl₃-δ (ppm): 0.88 (3H, m); 1.21 (6H, s); 1.31 (6H, m); 1.58(2H, m); 2.15 (2H, m); 2.59 (2H, m); 2.64 (2H, m); 2.88 (2H, s); 4.04(2H, m); 7.11 (1H, s); 7.16 (1H, s).

N.B.: acid H not observed.

Example 24 4-(6-hexyl-3-(hydroxyimino)-5-indanyloxy]butyric acid

A mixture of 50 mg (0.157 mmol) of 4-(6-hexyl-3-oxo-5-indanyloxy)butyricacid, 13 mg (0.188 mmol) of hydroxylamine hydrochloride and 32 mg (0.393mmol) of sodium acetate in 3 ml of 85% ethanol is heated at reflux for 1hour. After cooling, the mixture is poured into 50 ml of ice-cold water.The solid formed is isolated by filtration, washed with water and driedto give 26.3 mg (50%) of the expected product.

The compounds of Tables A and B below were prepared by following thesame types of procedures as in the preceding examples. TABLE A

Example m.p./° C. Y S¹⁰ S⁹ S¹¹ S¹² ¹H NMR(300 MHz) 1 O —C₆H₁₃—(CH₂)₃—COOH H H (CDCl₃)=0.87(3H, m); 1.31(2H, m); 2.15(2H, m);2.50-2.64(6H, m); 3.02(2H, m); 4.04(2H, m); 7.06-7.24(2H, 2s)-(OH notvisible) 2 CH₂ —C₆H₁₃ —(CH₂)₃—COOEt H H (DMSO-d6)=0.84(3H, m); 1.16(3H,m); 1.27(6H, m); 1.48(2H, m); 1.98(2H, m); 2.48(2H, m); 2.63-2.89(4H,m); 3.86-4.19(4H, m); 4.93(1H, m); 5.42(1H, s); 7.01(1H, s); 7.04(1H, s)3 O —C₆H₁₃

H H (CDCl₃)=0.87(3H, m); 1.26-1.45(6H, m); 1.48-1.74(2H, m+2H, s);2.55-2.85(4H, m); 3.04(2H, m); 3.92(3H, s); 5.15(2H, m); 7.18(1H, s);7.26(1H, s); 7.51(2H, m); 8.06(2H, m). 4 O —C₆H₁₃

H H (CDCl₃)=0.85(3H, m); 1.12-1.46(6H, m); 1.47-1.78(2H, m+2H, s);2.55-2.84(4H, m); 3.04(2H, m); 3.92(3H, s); 5.12(2H, m); 7.19(1H, s);7.26(1H, s); 7.39-7.71(2H, m); 7.89-8.22(2H, m). 5 O —C₆H₁₃—C(CH₃)₂—COOEt H H (CDCl₃)=0.88(3H, m); 1.15-1.44(3H, m+4H, m); 1.62(6H,s); 2.65(4H, m); 3.01(2H, m); 4.24(2H, m); 6.90(1H, s); 7.22(1H, s). 6 O—C₆H₁₃ —(CH₂)₄—C(CH₃)₂—COOEt H H (CDCl₃)=0.88(3H, m); 1.19-1.81(3H,m+6H, s+16H, m); 2.67(4H, m); 3.02(2H, m); 4.17(2H, m); 7.17(1H, s);7.21(1H, s). 7, (194) O —C₆H₁₃

H H (CDCl₃)=0.87(3H, m); 1.14-1.90(8H, m); 2.55-2.91(4H, m); 3.05(2H,m); 5.18(2H, s); 7.18(1H, s); 7.27(1H, s); 7.54(2H, m); 8.11(2H, m). 8,(90) O —C₆H₁₃ —C(CH₃)₂—COOH H H (CDCl₃)=0.88(3H, m); 1.32(6H, m);1.48-1.82(2H, m+6H, s); 2.67(4H, m); 3.03(2H, m); 7.07(1H, s); 7.24(1H,s). 9, (190) O —C₆H₁₃ —(CH₂)₃—COO⁻Na⁺ H H (DMSO-d6)=0.88(3H, m);1.31(6H, m); 1.57(2H, m); 1.99(2H, m); 2.44(2H, m); 2.64(4H, m);3.02(2H, m); 4.06(2H, m); 7.07(1H, s), 7.37(1H, s) 10 O —C₆H₁₃—(CH₂)₄—C(CH₃)₂—COOH H H (CDCl₃)=0.88(3H, m); 1.09-1.91(6H, s+14H, m);2.67(4H, m); 3.02(2H, m); 3.98(2H, m); 7.10(1H, s); 7.20(1H, s). 11 O—C₆H₁₃ —(CH₂)₂—C(CH₃)₂—COOEt H H (CDCl₃)=0.88(3H, m); 1.11-1.46(3H,m+6H, s+6H, m); 1.47-1.72(4H, m); 2.09(2H, m); 2.66(4H, m); 3.02(2H, m);4.11(2H, m); 7.09(1H, s); 7.20(1H, s). 12, (90) CH₂ —C₆H₁₃ —(CH₂)₃—COOHH H (CDCl₃)=0.87(3H, m); 1.31(6H, m); 1.57(2H, m); 2.13(4H, m); 2.63(4H,m); 3.22(2H, m); 4.07(2H, m); 6.80(1H, s); 7.19(1H, s). 13, (178-180) O—C₆H₁₃

H H (DMSO-d6)=0.80(3H, m); 1.24(6H, m); 1.57(2H, m); 2.55-2.84(4H, m);2.98(2H, m); 5.26(2H, s); 7.10-8.17(6H, aromatic, m). 14 O —C₆H₁₃—CH═CH—CH₂—COOEt H H (CDCl₃)=0.88(3H, m); 1.26(3H, m); 1.32(6H, m);1.60(2H, m); 2.70(4H, m); 3.05(2H, m); 3.28(2H, m); 4.16(2H, m);5.10(1H, m); 6.52(1H, m); 7.15-7.37(2H, 2s). 15, (98, 100) O —C₆H₁₃—CH₂—CH₂—C(CH₃)₂—COOH H H (CDCl₃)=0.88(3H, m); 1.15-1.47(6H, s+4H, m);1.61(2H, m); 2.13(4H, m); 2.67(4H, m); 3.02(2H, m); 4.06(2H, m);7.12(1H, s); 7.20(1H, s). 16 O —C₆H₁₃ —CH═CH—CH₂—COOH H H(CDCl₃)=0.87(3H, m); 1.15-1.48(6H, m); 1.60(2H, m); 2.58-2.81(4H, m);3.06(2H, m); 3.34(2H, m); 5.08(1H, m); 6.55(1H, m); 7.16-7.39(2H, 2s).17 O —C₆H₁₃ —CH₂—C(CH₃)₂—COOEt H H (CDCl₃)=0.87(3H, m); 1.21(3H, m);1.32(6H, s); 1.10-1.42(6H, m); 1.55(2H, m); 2.50-2.78(4H, m); 3.02(2H,m); 3.98(2H, s); 4.13(2H, m); 7.11(1H, s); 7.20(1H, s). 18 O —C₆H₁₃—(CH₂)₃—COOEt CH_(>>) CH₃ (CDCl₃)=0.88(3H, m); 1.10-1.43(3H, m+6H, s+4H,m); 1.60(2H, m); 2.16(2H, m); 2.39-2.77(4H, m); 2.64(2H, m); 2.87(2H,s); 4.02(2H, m); 4.14(2H, m); 7.09(1H, s); 7.15(1H, s). 19, (90) O—C₆H₁₃ —(CH₂)₃—COOH CH₃ CH₃ (CDCl₃)=0.88(3H, m); 1.10-1.44(6H, s+6H, m);1.58(2H, m); 2.62(4H, m); 2.88(2H, s); 4.04(2H, m); 7.11(1H, s);7.16(1H, s). 20 O —C₆H₁₃ —CH₂—C(CH₃)₂—COOH H H (CDCl₃)=0.88(3H, m);1.28(4H, m); 1.37(6H, s); 1.54(4H, m); 2.65(4H, m); 3.03(2H, m);4.00(2H, s); 7.12(1H, s); 7.21(1H, s). 21 O —C₆H₁₃ —(CH₂)₃—C(CH₃)₂—COOEtH H (CDCl₃)=0.87(3H, m); 1.06-1.43(3H, m+6H, s+6H, m); 1.43-1.88(6H, m);2.65(4H, m); 3.02(2H, m); 3.94(2H, m); 4.12(2H, m); 7.08(1H, s);7.20(1H, s). 22, (80) O —C₆H₁₃ —(CH₂)₃—C(CH₃)₂—COOH H H (CDCl₃)=0.88(3H,m); 1.25(6H, s); 1.31(4H, m); 1.43-1.91(8H, m); 2.67(4H, m); 3.02(2H,m); 3.97(2H, m); 7.09(1H, s); 7.20(1H, s). 23 O —C₆H₁₃—(CH₂)₄—C(CH₃)(Et)—COOEt H H (CDCl₃)=0.60-0.96(6H, m); 0.96-1.97(21H,m); 2.64(4H, m); 3.02(2H, m); 3.72-4.20(4H, m); 7.09(1H, s); 7.20(1H,s).

TABLE B

Example Y Q S¹¹ S¹² m.p. (° C.) ¹H NMR(300 MHz) 24

O —(CH₂)₃—COOH —C₆H₁₃ 148 (DMSO-d6): 0.84(3H, m); 1.27(6H, m); 1.49(2H,m); 1.94(2H, m); 2.40(2H, m); 2.53(2H, m); 2.74(2H, m); 2.86(2H, m);3.97(2H, m); 6.96(1H, s); 7.08(1H, s); 10.64(1H, broad s); 12.11(1H,broad s) 25

NH —(CH₂)₃—COOH

— (DMSO-d6): 1.78(2H, m); 2.27(2H, m); 2.70(2H, m); 2.73(2H, m);3.06(2H, m); 3.74(2H, s); 3.79(3H, s); 4.86(1H, broad m); 6.64(1H, s);6.73(1H, s); 6.86(1H, m); 7.02(2H, m); 7.21(1H, m); 10.51(1H, broad s);12.07(1H, broad s).

Example 30 Step a: 3-(3-iodo-4-methoxyphenyl)propionic acid

A mixture of 3-(4-methoxyphenyl)propionic acid (18 g; 0.1 mol), ICl (30g; 0.18 mol) and acetic acid (200 ml) is heated at +90° C. for 4 hours.

After concentration, the residue is taken up in ethyl acetate and washedwith 10% Na₂S₂O₃ solution (200 ml), and then with 1N sodium hydroxide.The aqueous phase, separated out by settling of the phases, is acidifiedto pH 1 and then extracted with ethyl acetate.

After drying (Na₂SO₄), evaporation of the solvents gives a beige powder(27.5 g, 90%).

¹H NMR-CDCl₃-δ(ppm): 2.63 (t, 2H); 2.85 (t, 2H); 3.84 (s, 3H); 6.74 (d,1H); 7.14 (dd, 1H); 7.62 (d, 1H).

Step b: 5-iodo-6-methoxyindan-1-one

Polyphosphoric acid (160 g; 1.63 mol) is preheated to +80° C., and3-(3-iodo-4-methoxyphenyl)propionic acid (10 g, 32.6 mmol) is then addedin four portions. The reaction mass is stirred for 40 minutes at +80° C.A mixture (600 g) of ice+water is then added and the resulting mixtureis extracted three times with ethyl acetate. The combined organic phasesare successively washed with water, with 1N sodium hydroxide and withbrine, and then dried (Na₂SO₄). Trituration of the evaporation residue(7.0 g) in a mixture of Et₂O/pentane (30 ml/15 ml) gives a brown powder(3.6 g).

The protocol is repeated twice for amounts of 5 g and 11.7 g of3-(3-iodo-4-methoxyphenyl)propionic acid to give, respectively, 1.2 gand 3.7 g of the expected product.

A second trituration of the total (8.5 g) in a mixture of ether/pentane(15 ml/4 ml) gives the pure expected product (7.7 g). The correspondingmother liquors are concentrated and purified by chromatography.Trituration in ether gives a second crop (1.1 g).

m.p.=140° C.

¹H NMR-CDCl₃-δ(ppm): 2.65-2.72 (m, 2H); 3.01-3.09 (m, 2H); 3.0 (s, 3H);7.09 (s, 1H); 7.96 (s, 1H).

Step c: 6-hydroxy-5-iodoindan-1-one

AlCl₃ (10.66 g; 80.0 mmol) is added to a mixture of5-iodo-6-methoxyindan-1-one (7.68 g; 26.66 mol) in toluene (130 ml).

After heating for 15 minutes at +80° C., the crude product is cooled andpoured into ice-cold water. The precipitate obtained is filtered off bysuction, washed with water and dried (6.36 g, 87% yield).

m.p.=260° C.

¹H NMR-DMSOd⁶-δ(ppm): 2.53-2.60 (m, 2H); 2.91-2.98 (m, 2H); 6.99 (s,1H); 7.96 (s, 1H); 10.65 (s, OH).

Step d: ethyl 4-(6-iodo-3-oxoindan-5-yloxy)butanoate

A mixture of 6-hydroxy-5-iodoindan-1-one (6.36 g, 23.2 mmol), caesiumcarbonate (15.12 g, 46.4 mmol) and ethyl 4-bromobutyrate (9.05 g, 46.4mmol) in acetone (60 ml) is heated at reflux pendant 1 hour 15 minutes.

The reaction mass is poured into ice-cold 0.5N hydrochloric acid. Afterextraction (EtOAc), washing with water and then drying (Na₂SO₄),chromatography on silica of the evaporation residue gives 5.28 g of theexpected product (59% yield).

¹H NMR-DMSOd⁶-δ(ppm): 1.17 (t, 3H); 1.99 (m, 2H); 2.52 (t, 2H);2.57-2.65 (m, 2H); 2.95-3.03 (m, 2H); 4.06 (q, 2H); 4.10 (t, 2H); 7.04(s, 1H); 8.07 (s, 1H).

Step e: 4-[6-(cyclohexylmethyl)-3-oxoindan-5-yloxy]butyric acid

A 0.5N solution of (cyclohexylmethyl)zinc bromide (1.42 ml, 0.708 mmol)in THF is added to a mixture of ethyl4-(6-iodo-3-oxoindan-5-yloxy)butanoate (250 mg, 0.644 mmol) anddichlorobis(triphenylphosphine)palladium II (23 mg) in DMF (3 ml) atroom temperature.

The mixture is stirred under nitrogen for 1 hour at room temperature andthen poured into ice-cold water. After extraction with ether, washingwith water and drying (Na₂SO₄), the evaporation residue (290 mg) ispurified by chromatography on silica (80/20 heptane/EtOAc).

138 mg of the expected product are obtained (yield: 60%).

The above product is taken up in methanol (2.5 ml) and treated with 1Nsodium hydroxide (0.77 ml) for 3 hours 30 minutes at room temperature.The reaction medium is diluted with water and then extracted with ethylacetate. The aqueous phase is acidified to pH 1 by addition of 1Nhydrochloric acid, and then extracted with ethyl ether. This ether phaseis concentrated and the residue is then dispersed in a 50/50 mixture ofheptane/diisopropyl ether (yield: 71%).

m.p.=130° C.

¹H NMR-DMSO d⁶-δ(ppm): 0.77-1.24 (5H, m); 1.37-1.73 (6H, m); 1.95 (2H,m) 2.40 (2H, m); 2.52 (2H, m); 2.58 (2H, m); 2.97 (2H, m); 4.01 (2H, m);7.02 (1H, s); 7.27 (1H, s); 12.12 (1H, s).

The compounds of Table C below are prepared from the product obtainedfrom step d) of the preparation of Example 30, or from the productobtained from step f) of the preparation of Example 66 illustratedbelow, following a procedure identical to that of Example 30. TABLE C

Example L m.p. (° C.) ¹H NMR(300 MHz) 26 —(CH₂)₂—C₆H₅ — (CDCl₃):1.98-2.31(2H, m); 2.44-2.78(4H, m); 2.80-3.18(6H, m); 3.96-4.22(2H, m);6.87-7.75(7H, m) 27 —(CH₂)₂—CH(CH₃)₂  84 (DMSO-d6): 0.91(6H, d,J=6.41Hz); 1.34-1.47(2H, m); 1.56(1H, sept., J=6.41Hz); 1.96(2H, m);2.29-2.45(2H, m); 2.54-2.69(4H, m); 2.87-3.06(2H, m); 4.02(2H, m);7.02(1H, s); 7.33(1H, s); 12.12(1H, s). 28

130 (DMSO-d6); 1.92(2H, m); 2.23(2H, m); 2.57(2H, m); 2.92(2H, m);3.76(3H, s); 3.92(2H, s); 4.02(2H, m); 6.61-7.40(6H, m); 12.10(1H, s) 29

130 (DMSO-d6); 1.92(2H, m); 2.31(2H, m); 2.58(2H, m); 2.96(2H, m);3.86-4.08(2H, s+2H, m); 6.80-7.56(6H, m); 12.11(1H, s) 30

130 (DMSO-d6); 0.77-1.24(5H, m); 1.37-1.73(6H, m); 1.95(2H, m); 2.40(2H,m); 2.52(2H, m); 2.58(2H, m); 2.97(2H, m); 4.01(2H, m); 7.02(1H, s);7.27(1H, s); 12.12(1H, s). 31

100 (DMSO-d6): 1.27(6H, s); 1.35-1.68(6H, m); 1.97(2H, m); 2.41(2H, m);2.53-2.76(4H, m); 2.97(2H, m); 4.02(2H, m); 7.03(1H, s); 7.35(1H, s);12.13(1H, s) 32 —(CH₂)₄—CN 150 (DMSO-d6): 1.46-1.75(4H, m); 1.97(2H, m);2.40(2H, m); 2.51(2H, m); 2.54-2.78(4H, m); 2.98(2H, m); 4.02(2H, m);7.04(1H, s); 7.35(1H, s); 12.12(1H, s) 33 —CH₂—CH₂—C≡CEt 120 (DMSO-d6):1.00(3H, m); 1.85-2.17(4H, m); 2.40(4H, m); 2.60(2H, m); 2.78(2H, m);2.97(2H, m); 4.03(2H, m); 7.04(1H, s); 7.38(1H, s); 12.14(1H, broad s).34 —CH₂—CH₂—C≡C—CH₃ 135 (DMSO-d6): 1.70(3H, s); 1.96(2H, m); 2.40(4H,m); 2.60(2H, m); 2.78(2H, m); 2.98(2H, m); 4.03(2H, m); 7.04(1H, s);7.37(1H, s); 12.15(1H, broad s).

Example 37 Step a: 5-bromo-6-nitroindan-1-one

Fuming nitric acid (166 ml) is cooled to −15° C., and 5-bromoindan-1-one(25 g, 0.118 mol) is then added portionwise. After stirring for 4 hours30 minutes at between −10° C. and −15° C., the reaction mass is pouredinto ice-cold water (1600 ml).

The precipitate is filtered off by suction, washed with water and takenup in dichloromethane to be dried over Na₂SO₄. The evaporation residue(25.8 g) is purified by crystallisation from ethanol (15.3 g, yield:51%).

m.p.=130° C.

¹H NMR-CDCl₃-δ(ppm): 2.75-2.82 (m, 2H); 3.18-3.25 (m, 2H); 7.89 (s, 1H);8.10 (s, 1H).

Step b: 5-hex-1-ynyl-6-nitroindan-1-one

1-Hexyne (7.3 g, 89.5 mmol) is added to a mixture, under nitrogen and atroom temperature, of 5-bromo-6-nitroindan-1-one (15.3 g, 59.7 mmol),dichlorobis(triphenylphosphine)palladium II (0.83 g, 1.19 mmol), CuI(1.14 g, 5.97 mmol) and triethylamine (14.8 ml) in THF (72 ml), at arate such that the temperature of the reaction mixture does not exceed40° C. After stirring for 1 hour between 35 and 40° C., catalyst (0.83g) and CuI (1.14 g) are added, and the mixture is stirred for a further1 hour 30 minutes between 35° C. and 40° C. The mixture is poured ontoether, the insoluble matter is filtered off, the filtrate isconcentrated and the evaporation residue is purified by chromatographyon alumina (8.2 g, yield: 53%).

¹H NMR-CDCl₃-δ(ppm): 0.93 (t, 3H); 1.39-1.70 (m, 4H); 2.44-2.52 (m, 2H);2.72-2.80 (m, 2H); 3.13-3.21 (m, 2H); 7.64 (s, 1H); 8.24 (s, 1H).

Step c: 6-amino-5-hex-1-ynylindan-1-one

A mixture of 5-hex-1-ynyl-6-nitroindan-1-one (8.2 g, 31.8 mmol), NH₄Cl(0.84 g) and Fe (8.88 g, 0.159 mol) in ethanol (97 ml) and water (32 ml)is heated at reflux for 45 minutes.

After concentrating to dryness, the residue is taken up in ether and theinsoluble matter is filtered off. The filtrate is washed with water,dried (Na₂SO₄) and concentrated. Dispersion in heptane gives a solid(6.2 g, yield: 86%).

¹H NMR-CDCl₃-δ(ppm): 0.95 (t, 3H); 1.41-1.68 (m, 4H); 2.50 (t, 2H);2.59-2.67 (m, 2H); 2.92-3.00 (m, 2H); 4.25 (broad s, 2H); 6.99 (s, 1H);7.33 (s, 1H).

Step d: 2,2,2-trifluoro-N-(6-hex-1-ynyl-3-oxoindan-5-yl)acetamide

Trifluoroacetic anhydride (6.88 g, 32.7 mmol) is added dropwise to amixture of 6-amino-5-hex-1-ynylindan-1-one (6.2 g, 27.3 mmol) intrifluoroacetic acid (37 ml), cooled to between 0° C. and 5° C. Thereaction mass is stirred for 1 hour 30 minutes at between 0 and 5° C.,and then poured onto ice-cold water. The precipitate is filtered off bysuction, washed with water and then dissolved in ether for drying(Na₂SO₄). Dispersion in heptane of the evaporation residue gives a solid(6.74 g, yield: 76%).

¹H NMR-CDCl₃-δ(ppm): 0.96 (t, 3H); 1.40-1.71 (m, 4H); 2.55 (t, 2H);2.67-2.76 (m, 2H); 3.04-3.13 (m, 2H); 7.53 (s, 1H); 8.64 (s, 1H), 8.82(broad s, NH).

Step e: (6-hex-1-ynyl-3-oxoindan-5-ylamino)acetic acid

A mixture of 2,2,2-trifluoro-N-(6-hex-1-ynyl-3-oxoindan-5yl)acetamide(2.8 g; 8.66 mol), methyl bromoacetate (5.3 g; 34.64 mmol), K₂CO₃ (4.7g, 34.64 mmol) and KI (1.44 g, 8.66 mmol) in acetone (84 ml) is heatedat reflux for 3 hours. After concentrating to dryness, the residue istaken up in ethyl ether and the insoluble matter is filtered off. Thefiltrate, once concentrated to dryness, is purified by chromatography onsilica. A light brown oil is obtained, which crystallises at roomtemperature (2.5 g, yield: 73%).

m.p.=80° C.

¹H NMR-CDCl₃-δ(ppm): 0.93 (t, 3H); 1.34-1.65 (m, 4H); 2.43 (t, 2H);2.69-2.77 (m, 2H); 3.09-3.17 (m, 2H); 3.75 (s, 3H); 3.80 (d, 1H); 5.00(d, 1H); 7.58 (s, 1H); 7.87 (s, 1H).

A solution of the above solid (2.5 g, 6.32 mmol) in methanol (92 ml) istreated overnight with an aqueous solution (46 ml) of NaOH (0.76 g,18.96 mmol) at room temperature. The medium is concentrated to drynessand the residue is taken up in water.

After acidification to pH 4.4 (pH-meter) with dilute HCl, theprecipitate formed is filtered off and then dissolved indichloromethane. This organic phase is dried over Na₂SO₄ and thenconcentrated to dryness. The solid obtained is dispersed in diisopropylether (1.65 g, 92%).

¹H NMR-DMSO d⁶-δ(ppm): 0.91 (t, 3H); 1.37-1.64 (m, 4H); 2.51-2.60 (m,4H); 2.85-2.95 (m, 2H); 3.92 (s, 2H); 5.66 (broad s, NH); 6.54 (s, 1H);7.37 (s, 1H).

Example 36 (6-Hexyl-3-oxoindan-5-ylamino)acetic acid

A solution in ethanol (50 ml) of the derivative from Example 48 (0.26 g,0.91 mmol) is treated with H₂ (3 bar) in the presence of 10% Pd/C (26mg). After filtering off the catalyst and evaporation of the solvent,the solid obtained is crystallised from diisopropyl ether (0.15 g,yield: 57%).

m.p.=144° C.

¹H NMR-CDCl₃-δ(ppm): 0.89 (t, 3H); 1.23-1.47 (m, 6H); 1.58-1.72 (m, 2H);2.58 (t, 2H); 2.62-2.70 (m, 2H); 2.96-3.05 (m, 2H); 4.04 (s, 2H); 5.99(broad s, NH); 6.82 (s, 1H); 7.18 (s, 1H).

Example 39 [(6-Hex-1-ynyl-3-oxoindan-5-yl)methylamino]acetic acid

A mixture of the derivative from Example 48 (1.37 g, 4.8 mmol), K₂CO₃(2.61 g, 19.2 mmol) and CH₃I (10.9 g, 76.8 mmol) in acetone (45 ml) isheated at reflux for 5 hours. CH₃I (10.9 g) is added and the mixture isstirred overnight at 50° C. CH₃I (10.9 g) is added and the mixture isheated at reflux for a further 4 hours 30 minutes. CH₃I (10.9 g), K₂CO₃(1.3 g) and DMF (10 ml) are added, and the mixture is stirred for afurther 3 days at room temperature. The reaction medium is thenconcentrated to dryness, the residue is taken up in ethyl ether and theinsoluble matter is filtered off. The filtrate is concentrated todryness and purified by chromatography on silica. A light brown oil isobtained (0.94 g, yield: 62%).

A solution of the oil obtained above (0.94 g, 3 mmol) in methanol (43ml) is treated overnight with an aqueous solution (21 ml) of NaOH (0.36g, 9 mmol). The medium is concentrated to dryness and the residue istaken up in water. After acidification to pH 4.4 (pH-meter) with diluteHCl, the medium is extracted with ether. The ether phase is dried overNa₂SO₄, filtered and concentrated.

The evaporation residue is dispersed in diisopropyl ether (0.5 g, 55%).

m.p.=160° C.

¹H NMR-CDCl₃-δ(ppm): 0.93 (3H, m); 1.32-1.71 (4H, m); 2.46 (2H, m); 2.69(2H, m); 2.91 (3H, s); 3.03 (2H, m); 3.99 (2H, s); 7.37 (1H, s); 7.49(1H, s).

Example 40 [(6-Hexyl-3-oxoindan-5yl)methylamino]acetic acid

A solution in ethanol (50 ml) of the derivative from Example 50 (0.27 g,0.91 mmol) is treated with H₂ (3 bar) in the presence of 10% Pd/C (27mg). After filtering off the catalyst and evaporation of the solvent,the solid obtained is taken up several times in boiling pentane.Evaporation of the pentane gives the expected product as a light yellowsolid (80 mg, yield: 30%).

m.p.=70° C.

¹H NMR-CDCl₃-δ(ppm): 0.88 (3H, m); 1.31 (6H, m); 1.64 (2H, m); 2.54-2.87(4H, m+3H, s); 3.06 (2H, m); 3.70 (2H, s); 7.32 (1H, s); 7.53 (1H, s).

The derivatives of Table D below are prepared according to theprocedures for the preparation of the derivatives of Examples 38, 39, 41and 42: TABLE D

Example S¹ P₁ S² m.p. (° C.) ¹H NMR(300 MHz) 35 —C≡C—(CH₂)₃—CH₃ H—(CH₂)₃—COOH — (CDCl₃): 0.91(3H, m); 1.32-1.67(4H, m) 1.88(2H, m);2.21-2.50(2H, m); 2.74(2H, m); 3.14(2H, m); 3.38(1H, m); 4.19(1H, m);7.37-7.76(2H.2s). 36 —C₆H₁₃ H —(CH₂)₃—COOH 110 (CDCl₃): 0.88(3H.m);1.15-1.48(6H, m); 1.61(2H, m); 2.00(2H, m); 2.33-2.58(4H, m); 2.65(2H,m); 2.99(2H, m); 3.25(2H, m); 5.42(2H, broad s); 6.90(1H, s); 7.13(1H,s) 37 —C≡C—C₄H₉ H —CH₂—COOH  80 (CDCl₃): 0.96(3H, m); 1.33-1.75(4H, m);2.52(2H, m); 2.67(2H, m); 2.98(2H, m); 4.04(2H, s); 4.27(2H, broad s);6.76(1H, s); 7.37(1H, s). 38 —C₆H₁₃ H —CH₂—COOH 144 (CDCl₃): 0.89(3H,m); 1.11-1.51(6H, m); 1.66(2H, m); 2.43-2.79(4H, m); 3.00(2H, m);4.04(2H, s); 5.98(2H, broad s); 6.82(1H, s); 7.18(1H, s) 39 —C≡C—C₄H₉CH₃ —CH₂—COOH 160 (CDCl₃): 0.93(3H, m); 1.32-1.71(4H, m); 2.46(2H, m);2.69(2H, m); 2.91(3H, s); 3.03(2H, m); 3.99(2H, s); 7.37(1H, s);7.49(1H, s) 40 —C₆H₁₃ CH₃ —CH₂—COOH  70 (CDCl₃): 0.88(3H, m); 1.31(6H,m); 1.64(2H, m); 2.54-2.87(4H, m+3H, s); 3.06(2H, m); 3.70(2H, s);7.32(1H, s); 7.53(1H.s). 41 —C₆H₁₃ —CH₃ —(CH₂)₃—COOH — (CDCl₃): 0.88(3H,m); 1.11-1.46(6H, m); 1.61(2H, m); 1.82(2H, m); 2.39(2H, m);2.51-2.79(3H, s+4H, m); 2.92(2H, m); 3.05(2H, m); 7.30(1H, s); 7.48(1H,s).

Example 42 Step a: 6-hexyl-3-oxoindan-5-yl1,1,1-trifluoromethanesulfonate

A mixture of 5-hexyl-6-hydroxyindan-1-one (4.5 g, 19.4 mmol) in pyridine(10 ml) is cooled to 10° C., and trifluoromethanesulfonic anhydride(6.01 g, 21.3 mmol) is then slowly added. After stirring for 1 hour atroom temperature, the crude reaction product is poured into a mixture of32% HCl (15 ml) and ice. After extraction with ether, the organic phaseobtained is washed with water, dried (Na₂SO₄) and concentrated. Theevaporation residue (7.08 g) is purified by flash chromatography (10/90ethyl acetate/heptane). 6.57 g of the expected product are obtained(yield: 93%).

¹H NMR-CDCl₃-δ(ppm): 0.88 (t, 3H); 1.23-1.45 (m, 6H); 1.57-1.72 (m, 2H);2.71-2.80 (m, 4H); 3.10-3.18 (m, 2H); 7.43 (s, 1H); 7.59 (s, 1H).

Step b: 5-hexyl-6-mercaptoindan-1-one

A suspension of NaH (60% in petroleum jelly, 0.72 g, 18.0 mmol) in THF(28 ml) is cooled to 0° C. and a solution of triisopropylsilanethiol(3.42 g, 18.0 mmol) in THF (28 ml) is then added. After stirring for 30minutes at 0° C., tetrakis(triphenylphosphine)palladium (1.6 g) isadded, followed by addition of a solution of the above triflate (6.54 g,18.0 mmol) in benzene (57 ml). The reaction mixture is then heated atreflux for 2 hours 30 minutes. It is cooled, poured onto ice andextracted with ether. The organic phase is washed with water and dried(Na₂SO₄). The crude product (10.0 g) from evaporation is purified byflash chromatography on silica (5/95 ethyl acetate/heptane) to give 5.17g of the expected silyl product (yield: 71%).

¹H NMR-CDCl₃-δ(ppm): 0.88 (t, 3H); 1.05 (d, 18H); 1.19-1.45 (m, 9H);1.56-1.69 (m, 2H); 2.62-2.69 (m, 2H); 2.91-2.99 (m, 2H); 3.01-3.08 (m,2H); 7.27 (s, 1H); 7.79 (s, 1H).

A solution of the above silyl derivative (5.17 g, 12.8 mmol) in THF (25ml) is cooled to 0° C. and 1M tetrabutylammonium fluoride solution (18ml, 18 mmol) is then added. After stirring for 5 minutes at 0° C., thecrude reaction product is poured into a mixture of 11% hydrochloric acidand ice, and extracted with ether. The organic phase is washed withwater and then dried (Na₂SO₄). The evaporation residue (6.3 g) isdispersed in heptane and then filtered off by suction. 1.9 g of theexpected product are obtained (yield: 60%).

m.p.=100° C.

¹H NMR-CDCl₃-δ(ppm): 0.89 (t, 3H); 1.26-1.46 (m, 6H); 1.56-1.69 (m, 2H);2.62-2.74 (m, 4H); 3.02-3.08 (m, 2H); 3.39 (s, 5H); 7.25 (s, 1H); 7.64(s, 1H).

Step c: ethyl 4-(6-hexyl-3-oxoindan-5-ylsulfanyl)butyrate

A mixture of the above thiol (0.3 g, 1.2 mmol), Cs₂CO₃ (0.41 g, 1.26mmol), and ethyl 4-bromobutyrate (0.259 g, 1.33 mmol) in acetone (4 ml)is heated at 55° C. for 2 hours. The crude reaction product is dilutedwith ether, washed with water and dried (Na₂SO₄). The evaporationresidue is purified by flash chromatography on silica (95/5heptane/ethyl acetate). 0.37 g of the expected product is obtained(yield: 85%).

¹H NMR-CDCl₃-δ(ppm): 0.88 (m, 3H); 1.24 (t, 3H); 1.25-1.45 (m, 6H); 1.61(m, 2H); 1.97 (m, 2H); 2.46 (t, 2H); 2.66 (m, 2H); 2.75 (m, 2H); 2.99(t, 2H); 3.06 (m, 2H); 4.13 (q, 2H); 7.26 (s, 1H); 7.60 (s, 1H).

Step d: 4-(6-hexyl-3-oxoindan-5-ylsulfanyl)butyric acid

A mixture of the product from step c (50 mg, 0.137 mmol), KOH (12 mg,0.214 mmol), water (0.5 ml) and methanol (1 ml) is stirred overnight atroom temperature. The crude reaction product is diluted with water andthen acidified with 1N HCl. The precipitate is filtered off by suctionand dried under vacuum (P₂O₅). 35 mg of the expected product areobtained (yield: 76%).

¹H NMR-CDCl₃-δ(ppm): 0.88 (3H, m); 1.19-1.47 (6H, m); 1.61 (2H, m); 1.98(2H, m); 2.53 (2H, m); 2.68 (2H, m); 2.76 (2H, m); 2.91-3.15 (4H, m);7.25 (1H, s); 7.61 (1H, s).

Example 43 4-(6-Hexyl-3-oxoindan-5-sulfonyl)butyric acid

A solution of the product from Example 51 (0.1 g, 0.276 mmol) indichloromethane (1 ml) is cooled to 0° C. and m-chloroperbenzoic acid(0.149 g, 70% pure, 0.60 mmol) is then added. The reaction mixture isstirred for 30 minutes at 0° C. and then for 2 hours 30 minutes at roomtemperature. The insoluble matter is filtered off. The filtrate iswashed with aqueous sodium bicarbonate solution and then with water, anddried (Na₂SO₄). 0.104 g (yield: 95%) of the sulfonyl product is obtainedin the form of an oil.

¹H NMR-CDCl₃-δ(ppm): 0.88 (m, 3H); 1.22 (t, 3H); 1.27-1.38 (m, 4H); 1.44(m, 2H); 1.70 (m, 2H); 1.99 (m, 2H); 2.44 (t, 2H); 2.74 (m, 2H); 3.05(m, 2H); 3.15-3.27 (m, 4H); 4.09 (q, 2H); 7.49 (s, 1H); 8.39 (s, 1H).

The above sulfone is treated for 18 hours with a mixture consisting ofKOH (20 mg, 0.356 mmol), methanol (2 ml) and water (1 ml). Afterdilution with water, the medium is extracted with ethyl ether. Theaqueous phase is acidified to pH 1 and then extracted with ethyl ether.After drying (Na₂SO₄), the evaporation residue is chromatographed onsilica (1/1 heptane/ethyl acetate). The oil obtained (32 mg) isdispersed in pentane. The desired product is obtained in the form of asolid (21 mg, yield: 24%).

m.p.=100° C.

¹H NMR-DMSO-d⁶-δ(ppm): 0.86 (3H, m); 1.19-1.47 (6H, m); 1.52-1.80 (4H,m); 2.33 (2H, m); 2.69 (2H, m); 3.01 (2H, m); 3.17 (2H, m); 3.37 (2H,m); 7.75 (1H, s); 8.03 (1H, s); 12.18 (1H, broad s).

The derivatives of Table E below are prepared using the same proceduresas those employed for the preparation of the derivative of Example 42starting with the product of step c: TABLE E

Example m S⁴ S⁵ m.p. (° C.) NMR 42 0 —C₆H₁₃ —(CH₂)₃—COOH 100 (CDCl₃):0.88(3H, m); 1.19-1.47(6H, m); 1.61(2H, m); 1.98(2H, m); 2.53(2H, m);2.68(2H, m); 2.76(2H, m); 2.91-3.15(4H, m); 7.25(1H, s); 7.61(1H, s) 432 —C₆H₁₃ —(CH₂)₃—COOH 100 (DMSO-d6): 0.86(3H, m); 1.19-1.47(6H, m);1.52-1.80(4H, m); 2.33(2H, m); 2.69(2H, m); 3.01(2H, m); 3.17(2H, m);3.37(2H, m); 7.75(1H, s); 8.03(1H, s); 12.18(1H, broad s). 44 0 —C₆H₁₃—CH₂—COOH 110 (DMSO-d6): 0.86(3H, m); 1.18-1.44(6H, m); 1.57(2H, m);2.69(2H, m); 2.73(2H, m) 3.01(2H, m); 3.84(2H, s); 7.41(1H, s); 7.50(1H,s); 12.80(1H, broad s). 45 0 —C₆H₁₃

150 (DMSO-d6): 0.83(3H, m); 1.15-1.37(6H, m); 2.53-2.76(2H, m); 2.58(2H,m); 2.66(2H, m); 3.00(2H, m); 4.33(2H, s); 7.32-7.46(2H, m);7.49-7.60(2H, m); 7.77(1H, m); 7.92(1H, m); 12.95(1H, broad s). 46 0—C₆H₁₃

135 (DMSO-d6): 0.84(3H, m) 1.11-1.36(6H, m); 1.47(2H, m); 2.58(2H, m);2.65(2H, m); 3.00(2H, m); 4.33(2H, s); 7.33-7.48(3H, m); 7.55(1H, s);7.84(2H, m); 12.89(1H, broad s). 47 0 —C₆H₁₃

 70 (DMSO-d6): 0.86(3H, m); 1.05(6H, s); 1.16-1.66(14H, m); 2.68(2H, m);2.70(2H, m); 2.97(4H, m); 7.39(1H, s); 7.45(1H, s); 12.03(1H, broad s).

Example 48 Step a: 3-hex-1-ynyl-4-methoxybenzaldehyde

A mixture of 3-iodo-4-methoxybenzaldehyde (5.2 g, 20 mmol),tetrakis(triphenylphosphine)palladium (0.29 g), CuI (0.38 g, 2 mmol) andtriethylamine (5 ml) in THF (25 ml) is cooled to +10° C., and 1-hexyne(3.5 ml, 30.5 mmol) is then added. The cooling bath is removed, and thetemperature of the reaction mixture rises slowly to +30° C. beforedecreasing slowly. 3 hours after the end of the addition, the crudereaction product is concentrated to dryness, and the residue obtained ispurified by flash chromatography on silica (15/85 ethylacetate/heptane). 4.1 g (yield: 95%) of the expected product areobtained.

¹H NMR-CDCl₃-δ(ppm): 0.94 (t, 3H); 1.41-1.67 (m, 4H); 2.47 (t, 2H); 3.94(s, 3H); 6.96 (d, 1H); 7.77 (dd, 1H); 7.89 (d, 1H); 9.83 (s, 1H).

Step b: 4-(3-hex-1-ynyl-4-methoxyphenyl)but-3-enoic acid

A mixture of the product of step a (6.6 g, 30.46 mmol),carboxyethyltriphenylphosphonium bromide (15.2 g, 36.6 mmol), THF (30ml) and DMSO (50 ml) is cooled to +5° C., and NaH (60% in petroleumjelly, 2.92 g, 73.0 mmol) is then added in two portions. The reactionmixture is stirred overnight at room temperature, cooled to +5° C. andthen hydrolysed by addition of 200 ml of water. The aqueous phase isbasified by addition of 1N sodium hydroxide, extracted with ether,acidified to pH 1 by addition of 35% hydrochloric acid, and thenextracted with ether. The resulting ether phase is washed with water,dried (Na₂SO₄) and concentrated. Flash chromatography on silica (50/50ethyl acetate/heptane) of the obtained residue gives the expectedproduct (5.15 g, yield: 62%).

m.p.=102° C.

¹H NMR-CDCl₃-δ(ppm): 0.94 (t, 3H); 1.41-1.67 (m, 4H); 2.46 (t, 2H); 3.26(d, 2H); 3.86 (s, 3H); 6.14 (dt, 1H); 6.40 (d, 1H); 6.78 (d, 1H); 7.22(dd, 1H); 7.41 (d, 1H).

Step c: 6-hexyl-7-methoxy-3,4-dihydro-2H-naphthalen-1-one

A mixture of the product from step b (4.5 g, 16.52 mmol) and 10% Pd/C(0.45 g) in ethanol (120 ml) is treated with H₂ (3 bar). Afterfiltration on Hyflow, the filtrate is concentrated to dryness (4.58 g).

¹H NMR-CDCl₃-δ(ppm): 0.88 (t, 3H); 1.23-1.42 (m, 6H); 1.48-1.62 (m, 2H);1.86-1.99 (m, 2H); 2.36 (t, 2H); 2.56 (t, 2H); 2.59 (t, 2H); 3.79 (s,3H); 6.75 (d, 1H); 6.94 (s, 1H); 6,95 (d, 1H).

The above oil is taken up in methanesulfonic acid (60 ml) and stirredovernight at room temperature. After hydrolysis with ice-cold water (120ml), the aqueous phase is extracted with dichloromethane. The organicphase is washed with water, dried (Na₂SO₄) and concentrated (4.3 g).

¹H NMR-CDCl₃-δ(ppm): 0.87 (t, 3H); 1.21-1.39 (m, 6H); 1.49-1.62 (m, 2H);2.04-2.15 (m, 2H); 2.56-2.64 (m, 4H); 2.86 (t, 2H); 3.84 (s, 3H); 6.99(s, 1H); 7.44 (s, 1H).

Step d: 6-hexyl-7-hydroxy-3,4-dihydro-2H-naphthalen-1-one

A mixture of the product obtained in step c (4.3 g, 16.45 mmol) andAlCl₃ (5.48 g, 41.1 mmol) in toluene (86 ml) is heated at reflux for 30minutes. The mixture is cooled to +5° C. and then hydrolysed withIce-cold water (200 ml). The aqueous phase, separated out by settling ofthe phases, is extracted twice with ethyl ether. The combined organicphases are washed with water, dried (Na₂SO₄) and then concentrated. Thesolid residue obtained (4.22 g) is recrystallised from cyclohexane. 3.95g of the expected product are obtained.

m.p.=125° C.

¹H NMR-CDCl₃-δ(ppm): 0.86 (t, 3H); 1.22-1.44 (m, 6H); 1.56-1.69 (m, 2H);2.04-2.15 (m, 2H); 2.63 (t, 2H); 2.65 (t, 2H); 2.85 (t, 2H); 6.99 (s,1H); 7.74 (s, 1H).

Step e: 4-(3-hexyl-8-oxo-5,6,7,8-tetrahydronaphtalen-2-yloxy)butyricacid

A mixture of the product from step d (100 mg, 0.406 mmol), K₂CO₃ (120mg, 0.88 mmol), KI (cat.) and methyl 4-chlorobutyrate (140 mg, 1.02mmol) in acetone (2 ml) is heated at reflux for 8 hours. 1N sodiumhydroxide (2 ml) is then added, and the mixture is heated at 60° C. for2 hours. The reaction mixture is poured into water, acidified to pH 1and then extracted with ethyl ether. The organic phase is washed withwater and concentrated. Recrystallisation from cyclohexane of theresidue obtained gives the expected product (40 mg).

m.p.=81° C.

¹H NMR—CDCl₃-δ(ppm): 0.87 (3H, m); 1.12-1.43 (6H, m); 1.53 (2H, m); 2.09(2H, m); 2.37-2.68 (4H, m); 2.85 (2H, m); 3.23 (2H, m); 3.59 (2H, m);4.03 (2H, m); 6.99 (1H, s); 7.40 (1H, s).

The derivatives of Table F below are prepared according to thepreparation procedure of Example 48: TABLE F

Example S⁶ m.p. (° C.) NMR(300 MHz) 48 —(CH₂)₃—COOH  81 (CDCl₃):0.87(3H, m); 1.12-1.43(6H, m); 1.53(2H, m); 2.09(2H, m); 2.37-2.68(4H,m); 2.85(2H, m); 3.23(2H, m); 3.59(2H, m); 4.03(2H, m); 6.99(1H, s);7.40(1H, s). 49 —CH₂—COOH 174 (CDCl₃): 0.87(3H, m); 1.14-1.45(6H, m);1.62(2H, m); 2.09(2H, m); 2.59(2H, m); 2.68(2H, m); 2.86(2H, m);4.67(2H, s); 7.02(1H, s); 7.33(1H, s) 50

150 (DMSO-d6): 0.80(3H, m); 1.08-1.44(6H, m); 1.55(2H, m); 1.99(2H, m);2.53(2H, m); 2.62(2H, m); 2.83(2H, m); 5.21(2H, s); 7.14(1H, s);7.41(1H, s), 7.52(1H, m); 7.68(1H, m); 7.89(1H, m); 8.06(1H, m);12.99(1H, broad s).

Example 52 Step a: N-(6-bromo-3-oxoindan-5-yl)-2,2,2-trifluoroacetamide

A mixture of 6-nitro-5-bromo-1-indanone (15.0 g, 58.6 mmol), iron (16.36g, 292.9 mmol) and NH₄Cl (1.56 g, 29.3 mmol) in ethanol (90 ml) andwater (30 ml) is heated at reflux for one hour. The reaction mixture isfiltered while hot and the insoluble matter is washed thoroughly withboiling ethanol. After concentrating to dryness, the residue is taken upin dichloromethane, washed with water and dried (Na₂SO₄). The expectedproduct is obtained after concentration (9.3 g, yield: 70%).

m.p.=220° C.

¹H NMR-DMSO d⁶-δ(ppm): 2.54 (m, 2H); 2.92 (m, 2H); 5.49 (s, NH₂); 6.98(s, 1H); 7.62 (s, 1H).

A solution of the above amine (9.3 g, 41.1 mmol) in trifluoroacetic acid(62 ml) is cooled to −5° C., and trifluoroacetic anhydride (10.35 g,49.3 mmol) is then added dropwise. The reaction mixture is stirred for 1hour 30 minutes at between −5 and 0° C. and then for 1 hour at roomtemperature, and is then poured into ice-cold water (800 ml). Theprecipitate is filtered off by suction, washed with water and taken upin dichloromethane for drying (Na₂SO₄). After concentration, 9 g (yield:68%) of the expected product are obtained.

¹H NMR-CDCl₃-δ(ppm): 2.74 (m, 2H); 3.14 (m, 2H); 7.79 (s, 1H); 8.57 (s,1H).

Step b: 4-[6-(4-fluorobenzyl 3-oxoindan-5-ylamino]butyric acid

4-Fluorobenzylzinc chloride, as a 0.5 M solution in THF (7.5 ml, 3.75mmol) is added dropwise to a mixture of the product from step a (0.365g, 1.13 mmol) and dichlorobis(triphenylphosphine)palladium II (40 mg) inDMF (5 ml). After stirring for 15 hours at room temperature, thereaction mixture is poured into ice-cold water (100 ml). The precipitateis filtered off by suction, washed with water and then taken up inmethylene chloride. The insoluble matter is filtered off. The filtrateis dried (Na₂SO₄) and then concentrated. Flash chromatography on silica(2/1 heptane/ethyl acetate) gives the expected coupling product (0.35 g,yield: 88%).

¹H NMR-CDCl₃-δ(ppm): 2.73 (m, 2H); 3.14 (m 2H); 4.02 (s, 2H); 6.98-7.15(m, 4H); 7.40 (s, 1H); 7.64 (broad s, NH), 8.07 (s, 1H).

The above coupling product (0.35 g, 1.0 mmol) is treated with a mixtureof ethyl 4-bromobutyrate (0.39 g, 2.0 mmol), K₂CO₃ (4.0 mmol, 0.54 g)and KI (0.16 g, 1 mmol), in acetone (9.6 ml) for 5 hours at reflux.

Ethyl 4-bromobutyrate (0.39 g) and KI (0.16 g) are added, and thereaction mass is stirred for a further 4 hours at reflux and thenconcentrated to dryness. The obtained residue is taken up in ethyl etherand the insoluble matter is filtered off. The concentrated filtrate ispurified by chromatography on silica (2/1 heptane/ethyl acetate). 0.17 gof the expected product is obtained (yield: 36%).

¹H NMR-CDCl₃-δ(ppm): 1.22 (t, 3H); 1.92 (m, 2H); 2.31 (m, 2H); 2.72 (m,2H); 2.92 (m, 1H); 3.09 (m, 2H); 3.86 (d, 1H); 3.96 (d, 1H); 4.09 (q,2H); 4.23 (m, 1H); 6.97-7.13 (m, 4H); 7.18 (s, 1H); 7.55 (s, 1H).

The ester thus obtained (0.17 g, 0.365 mmol) is then treated with amixture of NaOH (44 mg, 0.11 mol) in methanol (7.3 ml) and water (3.6ml) for 18 hours at room temperature. The solvents are evaporated offand the residue is taken up in water. After acidification to pH 3.8(pH-meter) with 1N hydrochloric acid, extraction with ethyl ether anddrying (Na₂SO₄), the evaporation residue obtained (110 mg) is purifiedby flash chromatography on silica (95/5 dichloromethane/methanol). Ayellow solid is obtained (90 mg, 72%).

m.p.=144-145° C.

¹H NMR-CDCl₃-δ(ppm): 1.84 (m, 2H); 2.29 (t, 2H); 2.62-2.69 (m, 2H);2.96-3.02 (m, 2H); 3.15 (t, 2H); 3.86 (s, 2H); 5.08 (broad s, NH andCO₂H); 6.90-7.03 (m, 3H); 7.05-7.15 (m, 3H).

Example 54 4-[6-(4-Fluorophenyl)-3-oxoindan-5-ylamino]butyric acid

A mixture of the product obtained in step a of Example 63 (0.5 g, 1.55mmol), tetrakis(triphenylphosphine)palladium (46 mg), Na₂CO₃ (0.33 g,3.11 mmol), water (1.2 ml), toluene (6.8 ml) and p-fluorophenylboronicacid (0.24 g, 1.72 mmol) is heated at reflux for 3 hours. Catalyst (46mg), Na₂CO₃ (66 mg) and p-fluorophenylboronic acid (48 mg) are added,and the reaction mass is stirred for a further one hour at reflux. Afteraddition of ethyl ether, the organic phase is washed with water, dried(Na₂SO₄) and concentrated. Flash chromatography (1/1 heptane/ethylacetate) gives a vitreous solid (0.59 g), which is dispersed in a 2/1mixture of heptane/ethyl acetate to give 0.37 g (yield: 71%) of thedesired coupling product.

¹H NMR-CDCl₃-δ(ppm): 2.73-2.80 (m, 2H); 3.13-3.20 (m, 2H); 7.22-7.27 (m,2H); 7.31-7.38 (m, 2H); 7.42 (s, 1H); 7.84 (broad s, NH); 8.53 (s, 1H).

The above coupling product (0.37 g, 1.1 mmol) is treated with a mixtureof ethyl 4-bromobutyrate (0.43 g, 2.2 mmol), K₂CO₃ (0.6 g, 4.4 mmol) andKI (0.18 g, 1.1 mmol) in acetone (10.6 ml) for 5 hours at reflux. Thebromo ester (0.43 g) and KI (0.18 g) are added, and the reaction mass isstirred for a further 4 hours at reflux, followed by concentrating todryness. The residue obtained is taken up in ethyl ether and theinsoluble matter is filtered off. The concentrated filtrate is purifiedby chromatography on silica (3/1 heptane/ethyl acetate). 0.28 g of theexpected product is obtained (56%).

¹H NMR—CDCl₃-δ(ppm): 1.19 (t, 3H); 1.63-1.79 (m, 2H); 2.06-2.31 (m, 2H);2.56 (m, 1H); 2.74-2.83 (m, 2H); 3.18-3.25 (m, 2H); 3.80 (m, 1H); 4.04(q, 2H); 7.09-7.18 (m, 2H); 7.25-7.31 (m, 2H); 7.52 (s, 1H); 7.59 (s,1H).

The ester thus obtained (0.28 g, 0.62 mmol) is then treated with amixture of sodium hydroxide (74 mg, 1.85 mmol) in methanol (12.4 ml) andwater (6.2 ml) for 18 hours at room temperature. The solvents areevaporated off and the residue is taken up in water. After acidificationto pH 4.2 with 1N hydrochloric acid, extraction with ethyl ether anddrying (Na₂SO₄), the evaporation residue obtained (180 mg) is purifiedby flash chromatography on silica (95/5 dichloromethane/methanol). Ayellow solid is obtained (150 mg, 75%).

m.p.=148-150° C.

¹H NMR-CDCl₃-δ(ppm): 1.89 (m, 2H); 2.40 (t, 2H); 2.65-2.72 (m, 2H);3.00-3.06 (m, 2H); 3.18 (t, 2H); 6.96 (s, 1H); 7.10-7.18 (m, 3H);7.31-7.39 (m, 2H).

The derivatives of Table G below are prepared by following theprocedures for the preparation of the derivatives of Example 52 andExample 54: TABLE G

Example S⁷ m.p. (° C.) ¹H NMR(300 MHz) 51

149-151 (CDCl₃): 1.72-2.04(2H, m); 2.27-2.57(2H, m); 2.57-2.82(2H, m);2.90-3.10(2H, m); 3.10-3.36(2H, m); 4.49-6.48(2H, broad s); 6.99(1H, s);7.14(1H, s); 7.35-7.61(2H, m); 7.61-7.86(2H, m). 52

144-145 (CDCl₃): 1.84(m, 2H); 2.29(t, 2H); 2.62-2.69(m, 2H);2.96-3.02(m, 2H); 3.15(t, 2H); 3.86(s, 2H); 5.08(broad s, NH and CO₂H);6.90-7.03(m, 3H); 7.05-7.15(m, 3H). 53

165-167 (CDCl₃): 1.74-1.99(2H, m); 2.21-2.40(2H, m); 2.51-2.73(2H, m);2.88-3.07(2H, m); 3.09-3.24(2H, m); 3.73-3.87(2H, m); 3.88(3H, s);6.80-6.94(3H, m); 6.96-7.06(1H, m); 7.11-7.23(2H, m). 54

148-150 (CDCl₃): 1.89(m, 2H); 2.40(t, 2H); 2.65-2.72(m, 2H);3.00-3.06(m, 2H); 3.18(t, 2H); 6.96(s, 1H); 7.10-7.18(m, 3H);7.31-7.39(m, 2H). 55

132 (DMSO-d6): 1.76(2H, m); 2.21(2H, m); 2.48(2H, m); 2.89(2H, m);3.08(2H, m); 3.92(2H, s); 5.27(1H, broad m); 6.66(1H, s); 7.08(2H, m);7.32(2H, m); 12.06(1H, broad s). 56

168 (DMSO-d6): 1.75(2H, m); 2.22(2H, m); 2.52(2H, m); 2.90(2H, m);3.08(2H, m); 3.96(2H, s); 5.26(1H, broad m); 6.67(1H, s); 6.82-7.24(4H,m); 12.02(1H, broad s). 57

158 (DMSO-d6): 1.99(2H, m); 2.41(2H, m); 2.49(3H, s); 2.84(2H, m);3.18(2H, m); 3.31(2H, m); 4.05(2H, s); 7.09(1H, s); 7.15-7.38(4H, m);7.43(1H, s) NB: 2H, exchangeable, very broad s from 3.0 to 5.0. 58

160 (DMSO-d6): 1.76(2H, m); 2.24(2H, m); 2.51(2H, m); 2.86(2H, m);3.07(2H, m); 3.71(3H, s); 3.83(2H, s); 5.11(1H, broad m); 6.65(1H, s);6.86(2H, m); 6.99(1H, s); 7.15(2H, m); 12.08(1H, very broad s). 59

146 (DMSO-d6): 1.29(3H, m); 1.76(2H, m); 2.24(2H, m); 2.51(2H, m);2.86(2H, m); 3.07(2H, m); 3.83(2H, s); 3.97(2H, m); 5.11(1H, broad m);6.65(1H, s); 6.84(2H, m); 6.99(1H, s); 7.12(2H, m); 12.09(1H, very broads). 60

158 (DMSO-d6): 0.93-1.71(8H, m); 1.80(2H, m); 1.99(1H, m); 2.31(3H, m);2.44(2H, m); 2.69(1H, m); 2.92(2H, m); 3.10(2H, m); 4.93(1H, broad m);6.61(1H, s); 7.21(1H, s); 12.04(1H, broad s). 61

— (DMSO-d6): 1.65(2H, m); 2.05(3H, s); 2.18(2H, m); 2.59(2H, m);2.95(2H, m); 3.07(2H, m); 4.21(1H, broad m); 6.78(1H, s); 7.06(1H, s);7.11(1H, m); 7.21-7.45(3H, m); 12.05(1H, very broad s). 62

— (DMSO-d6): 1.70(2H, m); 2.23(2H, m); 2.36(3H, s); 2.60(2H, m);2.95(2H, m); 3.07(2H, m); 4.66(1H, broad m); 6.77(1H, s); 7.15(1H, s);7.16-7.27(3H, m); 7.37(1H, m); 12.07(1H, very broad s). 63

— (DMSO-d6): 1.70(2H, m); 2.24(2H, m); 2.26(6H, s); 2.58(2H, m);2.93(2H, m); 3.09(2H, m); 4.64(1H, broad m); 6.75(1H, s); 7.13(1H, s);7.14-7.33(3H, m); 12.05(1H, very broad s). 64

— (DMSO-d6): 1.71(2H, m); 2.24(2H, m); 2.58(2H, m); 2.95(2H, m);3.07(2H, m); 3.79(3H, s); 4.75(1H, broad m); 6.77(1H, s); 6.98(1H, m);7.18(1H, s); 7.40(1H, m); 7.47-7.73(2H, m); 12.05(1H, very broad s). 65

— (DMSO-d6): 1.71(2H, m); 2.23(2H, m); 2.58(2H, m); 2.95(2H, m);3.06(2H, m); 3.80(3H, s); 4.67(1H, broad m); 6.75(1H, s); 7.05(2H, m);7.13(1H, s); 7.35(2H, m); 12.08(1H, very broad s).

Example 66 Step a: Ethyl 3-(3-bromo-4-methoxyphenyl)propanoate

87.5 g of bromine are added dropwise at 25° C. over 3 hours to asolution of ethyl 3-(4-methoxyphenyl)propanoate (113.9 g; 0.545 mol) in900 ml of chloroform. The mixture is poured into water and the organicphase is separated out by settling of the phases and washed with 10%sodium hydrosulfite solution. After drying and evaporating off thesolvents, a yellow oil is collected (154 g; 98%).

¹H NMR-CHCl₃-δ(ppm): 1.22 (3H, m); 2.56 (2H, m); 2.85 (2H, m); 3.85 (3H,s); 4.11 (2H, m); 6.81 (1H, m); 7.09 (1H, m); 7.38 (1H, m).

Step b: 3-(3-Bromo-4-methoxyphenyl)propanoic acid.

154 g (0.535 mol) of ethyl 3-(3-bromo-4-methoxyphenyl)propanoate aremixed with 45 g (0.8 mol) of potassium hydroxide, 600 ml of methanol and300 ml of water. The mixture is heated at reflux for 3 hours, and themethanol is then evaporated off. The solution obtained is washed withether; the aqueous phase is acidified and extracted with ether. Theorganic phase is dried (Na₂SO₄), and the solvents are evaporated off:white solid (132.7 g; 96%).

¹H NMR-CHCl₃-δ (ppm): 2.64 (2H, m); 2.87 (2H, m); 3.86 (3H, s); 6.82(1H, m); 7.10 (1H, m); 7.39 (1H, m); 11.17 (1H, very broad s).

Step c: 3-(3-Bromo-4-methoxyphenyl)propanoyl chloride

A solution of 102.4 g (0.86 mol) of thionyl chloride is added to asolution of 51.8 g (0.2 mol) of 3-(3-bromo-4-methoxyphenyl)propanoicacid in 700 ml of chloroform. The mixture is heated at reflux for 4hours, and the solvent is then evaporated off. 53 g are obtained.

¹H NMR-CHCl₃-δ (ppm): 2.92 (2H, m); 3.16 (2H, m); 3.87 (3H, s); 6.83(1H, m); 7.10 (1H, m); 7.37 (1H, m).

Step d: 5-Bromo-6-methoxyindan-1-one

48 g (0.18 mol) of 3-(3-bromo-4-methoxyphenyl)propanoyl chloride aredissolved in 500 ml of dichloromethane. 72 g (0.54 mol) of aluminiumchloride are added in small amounts. The reaction medium is stirred for2 hours and then poured into water and the phases are separated bysettling. The organic phase is dried (Na₂SO₄) and the solvent isevaporated off: (39.8 g). The product is triturated in ethanol, filteredoff and dried (25 g; 63%)

¹H NMR-CHCl₃-δ (ppm): 2.69 (2H, m); 3.05 (2H, m); 3.91 (3H, s); 7.17(1H, s); 7.68 (1H, s).

Step e: 5-Bromo-6-hydroxyindan-1-one

46.7 g (0.35 mol) of aluminium chloride are added portionwise to asolution of 28.3 g (0.117 mol) of 5-bromo-6-methoxyindan-1-one in 500 mlof toluene. The reaction mixture is heated at reflux for 15 minutes andis then poured into water and the phases are separated by settling(sparingly soluble product).

The suspended solid is filtered off and the solvents are evaporated off.The solid residue is purified by flash chromatography (98/2CH₂Cl₂/MeOH), and 22 g of solid are obtained (83%); m.p.=210° C.

¹H NMR-CHCl₃-δ (ppm): 2.69 (2H, m); 3.06 (2H, m); 5.73 (1H, s); 7.33(1H, s); 7.63 (1H, s).

Step f: ethyl 4-(6-bromo-3-oxoindan-5-yloxy)butyrate

A mixture of 4.2 g (0.0185 mol) of 5-bromo-6-hydroxyindan-1-one, 150 mlof acetone and 9 g (0.0276 mol) of caesium carbonate is heated for 30minutes at 56° C. 5.4 g (0.227 mol) of ethyl 4-bromobutyrate are addeddropwise and the mixture is then heated at reflux for 7 hours.

The resulting mixture is poured into 1N hydrochloric acid solution andextracted with ether. The organic phase is dried (Na₂SO₄) and thesolvents are evaporated off. The residue is triturated in hexane: solid,m.p.=95° C. (5 g; 79%).

¹H NMR-CHCl₃-δ (ppm): 1.25 (3H, m); 2.17 (2H, m); 2.57 (2H, m); 2.70(2H, m); 4.09 (2H, m); 4.14 (2H, m); 7.16 (1H, s); 7.69 (1H, s).

Step g: ethyl4-[3-oxo-6-(4-trifluorormethylphenyl)indan-5-yloxy]butyrate

A mixture of 1.2 g (3.5 mmol) of ethyl4-(6-bromo-3-oxoindan-5-yloxy)butyrate, 25 ml of toluene, 3.9 ml ofsodium bicarbonate solution (at 2 mol per litre), 5 ml of ethanol, 0.8 g(42 mmol) of 4-(trifluoromethyl)phenylboronic acid and 77 mg (0.007mmol) of tetrakis(triphenylphosphine)palladium (0) is heated at refluxfor 2 hours. The mixture is poured into a mixture of 30 ml of water, 8ml of aqueous ammonia and 10 ml of sodium carbonate solution (2 mol perlitre). The resulting mixture is extracted with ether and, after dryingand evaporation, 1.4 g of product purified by flash chromatography (98/2dichloromethane/methanol) (1.22 g, 84%) are collected.

¹H NMR-CHCl₃-δ (ppm): 1.23 (3H, m); 2.04 (2H, m); 2.36 (2H, m); 2.74(2H, m); 3.11 (2H, m); 4.04 (2H, m); 4.10 (2H, m); 7.28 (1H, s); 7.39(1H, s); 7.56-7.85 (4H, m).

Step h: 4-[3-oxo-6-(4-trifluoromethylphenyl)indan-5-yloxy]butyric acid

1.2 g (3 mmol) of ethyl4-[3-oxo-6-(4-trifluoromethylphenyl)indan-5-yloxy]butyrate are mixedwith 250 mg (45 mmol) of potassium hydroxide, 40 ml of methanol and 10ml of water. The mixture is heated at reflux for 2 hours and themethanol is then evaporated off. The solution obtained is washed withether; the aqueous phase is acidified and extracted withdichloromethane. The organic phase is dried (Na₂SO₄) and the solventsare evaporated off: yellow solid (0.95 g). Purification of the compoundby flash chromatography (98/2 dichloromethane/methanol) [lacuna] (0.56g; 50%).

¹H NMR-CHCl₃-δ (ppm): 2.05 (2H, m); 2.42 (2H, m); 2.75 (2H, m); 3.11(2H, m); 4.06 (2H, m); 7.28 (1H, s); 7.39 (1H, s); 7.55-7.77 (4H, m)

N.B.: acid H not observed.

Examples 67 to 69

The additional Examples 67 to 69, prepared from the compound obtained asan intermediate in step f) of Example 66, are collated in Table H below.TABLE H

Example S⁸ S⁹ ¹H NMR(300 MHz) 67 4-fluorophenyl H (DMSO-d6):1.76-2.04(2H, m); 2.21-2.35(2H, m); 2.59-2.73(2H, m); 2.94-3.12(2H, m);3.95-4.16(2H, m); 7.15-7.33(3H, m); 7.45-7.64(3H, m); 12.13(1H, broads). 68 4-trifluoromethylphenyl C₂H₅ (CDCl₃): 0.99-1.23(3H, m);1.80-2.02(2H, m); 2.13-2.32(2H, m); 2.50-2.71(2H, m); 2.86-3.09(2H, m);3.78-4.11(4H, m); 7.07-7.21(2H, m); 7.42-7.68(4H, m). 693,4-dichlorophenyl H (CDCl₃): 1.95-2.17(2H, m); 2.37-2.58(2H, m);2.67-2.86(2H, m); 3.05-3.22(2H, m); 3.95-4.18(2H, m); 7.27-7.30(1H, m);7.32-7.40(2H, m); 7.45-7.52(1H, m); 7.60-7.64(1H, m).

Example 70

Step a:

A suspension of 6-hydroxy-5-methoxy-1-indanone (1.5 g; 8.42 mmol) inpyridine (4 ml) is cooled to 0° C., followed by addition oftrifluoromethanesulfonic anhydride (1.6 ml; 9.51 mmol; 1.1 eq). Themixture is stirred for 1 hour and then poured into ice-cold 2Nhydrochloric acid. The aqueous phase is extracted three times with ethylacetate. The combined organic phases are washed with brine, dried andconcentrated.

Flash chromatography (30% EtOAc/heptane) gives the expected product(1.34 g, yield: 51%) as a beige powder.

¹H NMR-CDCl₃-δ (ppm): 2.63-2.79 (2H, m); 3.04-3.22 (2H, m); 4.00 (3H,s); 7.06 (1H, s); 7.58 (1H, s).

Step b:

Hexylzinc bromide, as a 0.5N solution in tetrahydrofuran (14 ml; 7 mmol;1.63 eq), is added quickly to a mixture, under nitrogen and at roomtemperature, of the product obtained from step a (1.34 g; 4.32 mmol) anddichlorobis(triphenylphosphine)palladium II (110 mg) in dry DMF (20 ml).

The reaction is slightly exothermic and the temperature of the reactionmixture rises to 37° C. After stirring for 35 minutes, the mixture ispoured into ice-cold water (100 ml) comprising 1 N hydrochloric acid (10ml) and ether.

The insoluble matter is filtered off and the aqueous phase is extractedtwo more times with ether. The combined organic phases are washed withwater, dried and concentrated.

Flash chromatography (20% EtOAc/heptane) gives the expected product (0.2g, yield: 19%) in the form of a beige powder.

¹H NMR-CDCl₃-δ (ppm): 0.76-0.98 (3H, m); 1.15-1.41 (4H, m); 1.45-1.71(4H, m); 2.49-2.74 (4H, m); 2.98-3.17 (2H, m); 3.89 (3H, s); 6.83 (1H,s); 7.52 (1H, s).

Step c:

A mixture in toluene (5 ml) of the product obtained from step b (0.2 g;0.81 mmol) and AlCl₃ (0.27 g; 2.0 mmol; 2.5 eq) is heated in a bath at100° C. for 2 hours. The mixture is poured into ice-cold watercomprising concentrated hydrochloric acid and diethyl ether. The aqueousphase is extracted two more times with diethyl ether. The combinedorganic phases are washed with water, dried and concentrated. A beigepowder is obtained (0.14 g).

¹H NMR-CDCl₃-δ (ppm): 0.76-0.96 (3H, m); 1.16-1.45 (4H, m); 1.48-1.71(4H, m); 2.54-2.72 (4H, m); 2.96-3.13 (2H, m); 6.74-6.89 (1H, broad s);6.82 (1H, s); 7.55 (1H, s).

Step d: 4-(6-Hexyl-1-oxoindan-5-yloxy)butyric acid

A mixture of the product obtained from step c (0.14 g, 0.60 mmol), ethyl4-bromobutyrate (0.18 g; 0.92 mmol; 1.5 eq) and caesium carbonate (0.30g; 0.92 mmol; 1.5 eq) in acetone (2 ml) is heated at reflux for 7 hours.The mixture is then poured into water and diethyl ether. The aqueousphase is extracted twice with diethyl ether. The combined organic phasesare washed with water, dried and concentrated.

Flash chromatography (30% EtOAc/heptane) gives the product in the formof a brown oil (50 mg, yield: 24%).

This product is taken up in methanol (2 ml) and treated with 1 N sodiumhydroxide (0.4 ml) for one hour. The mixture is poured into ice-cold 1 Nhydrochloric acid and diethyl ether. The aqueous phase is extracted twomore times with diethyl ether. The combined organic phases are washedwith water and dried. The evaporation residue is recrystallised fromcyclohexane. The expected product is obtained in the form of colourlessbright crystals (16.7 mg).

m.p.=122° C.

¹H NMR-CDCl₃-δ (ppm): 0.76-0.97 (3H, m); 1.11-1.92 (8H, m); 2.06-2.29(2H, m); 2.48-2.73 (6H, m); 2.92-3.12 (2H, m); 3.96-4.24 (2H, m); 6.81(1H, s); 7.52 (1H, s).

Among the compounds that are especially preferred are:

Compounds 71-176 were prepared according to the same types of proceduresas in the preceding examples. No. structure MW mass NMR 71

316.40 ¹H NMR(300 MHz, CDCl₃)□ppm: 1.3(m, 6H), 1.8(m, 4H), 2.2(dd,J=13.0, 6.2Hz, 2H), 2.6(m, 4H), 3.0(m, 3H), 4.0(t, J=5.8Hz, 2H), 7.1(s,1H) 7.3(s, 1H) 72

302.41 ¹H NMR(300 MHz, DMSO-D₆) □ ppm: 0.8(t, J=6.5Hz, 3H), 1.2(m, 4H),1.4(m, 2H), 1.9(m, 2H), 2.4(m, 6H), 2.9(m, 2H), 3.9(t, J=6.1Hz, 2H),6.9(s, 1H), 7.2(s, 1H) 12.0(s, 1H) 73

332.44 ES+ 333.3 ES− 331.3 74

332.44 ES+ 333.3 ES− 331.3 75

338.83 ES+ 339.2/341.2 ES− 337.2/339.2 76

316.40 ES+ 317.3 ES− 315.3 77

352.43 ¹H NMR(300 MHz, DMSO-D₆) □ ppm: 1.3(m, 8H), 1.7(m, 2H), 2.0(m,2H), 2.5(m, 5H), 3.0(m, 2H), 3.3(m, 4H), 4.0(t, J=6.1Hz, 2H), 7.0(s,1H), 7.3(s, 1H), 12.1(s, 1H) 78

344.45 ¹H NMR(300 MHz, CDCl₃) □ppm: 1.9(m, 2H), 2.1(m, 2H), 2.6(m, 8H),3.0(m, 2H), 4.0(m, 2H), 7.2(m, 7H) 79

379.24 ES+ 379.3/381.3 80

378.35 ES+ 379.2 81

378.35 ES+ 379.2 82

394.34 ES+ 395.3 83

340.37 ES+ 341.3 84

344.79 ES+ 345.2/347.2 ES− 343.2/345.2 85

378.35 ES+ 379.3 86

394.34 ES− 393.3 87

366.29 ES− 365.3 88

290.36 ¹H NMR(300 MHz, CDCl₃) □ppm: 0.9(t, J=6.6Hz, 3H), 1.3(m, 6H),1.6(m, 2H), 2.7(m, 4H), 3.0(m, 2H), 4.8(s, 2H), 7.1(s, 1H), 7.3(s, 1H)89

310.35 ¹H NMR(300 MHz) □ ppm: 2.6(m, 2H), 2.9(m, 6H), 4.7(d, J=6.3Hz,2H), 7.1(m, 7H) 90

286.33 ES+ 287.3 ES− 285.3 91

406.40 ES+ 407.2 92

378.35 ES− 377.2 93

379.24 ES− 377.1/379.1/381.1 94

344.79 ES− 343.3/345.3 95

378.35 ES− 377.2 96

324.38 ES+ 325.2 ES− 323.2 97

340.37 ES− 339.2 98

352.39 ES+ 353.2 ES− 351.2 99

394.34 ES− 393.2 100

346.33 ES+ 347.2 ES− 345.2 101

360.41 ES+ 361.2 ES− 359.2 102

328.34 ES+ 329.2 ES− 327.2 103

338.40 ES+ 339.2 ES− 337.2 104

370.40 ES+ 371.2 ES− 369.2 105

328.34 ES+ 329.2 ES− 327.2 106

324.38 ES+ 325.2 ES− 323.2 107

352.39 ES− 351.2 108

335.36 ES− 334.2 109

346.33 ES− 345.2 110

346.33 ES− 345.2 111

342.37 ES− 341.2 112

338.40 ES+ 339.2 ES− 337.2 113

374.82 ES− 373.1/375.1 114

388.85 ES− 387.2/389.2 115

382.46 ES+ 383.2 ES− 381.2 116

368.43 ES+ 369.2 ES− 367.2 117

354.40 ES+ 355.2 ES− 353.2 118

446.34 ES− 445.2 119

304.39 ES+ 305.3 ES− 303.3 120

333.43 ES+ 334.3 ES− 332.3 121

305.37 ¹H NMR(300 MHz, CDCl₃) □ppm: 0.9(t, J=6.6Hz, 3H), 1.3(m, 6H),1.6(m, 2H), 2.7(m, 2H), 3.0(m, 4H), 4.8(s, 2H), 7.0(s, 1H), 7.1(s, 1H),7.3(s, 1H) 122

325.36 ¹H NMR(300 MHz) □ ppm: 2.9(m, 8H), 4.8(s, 2H), 7.0(s, 1H), 7.3(m,7H), 10.8(s, 1H) 123

329.40 ¹H NMR(300 MHz, DMSO-d₆) □ ppm: 1.0(t, J=7.4Hz, 3H), 2.0(m, 4H),2.4(m, 4H), 2.8(m, 6H), 4.0(t, J=6.3Hz, 2H), 7.0(s, 1H), 7.1(s, 1H),10.7(s, 2H) 124

301.34 ES+ 302.3 ES− 300.3 125

324.38 ES+ 325.2 ES− 323.2 126

378.35 ES+ 379.3 ES− 377.3 127

394.34 ES+ 395.3 128

340.37 ES+ 341.3 ES− 339.3 129

340.37 ES+ 341.3 130

354.36 ES+ 355.3 131

344.79 ES− 343.3/345.3 132

394.34 ES+ 395.2 ES− 393.2 133

346.33 ES− 345.2 134

360.41 ES− 359.2 135

328.34 ES− 327.2 136

338.40 ES+ 339.2 ES− 337.2 137

370.40 ES+ 371.2 ES− 369.2 138

324.38 ES+ 325.2 ES− 323.2 139

352.39 ES− 351.2 140

335.36 ES+ 336.2 ES− 334.2 141

368.43 ES+ 369.2 ES− 367.2 142

338.40 ES+ 339.2 143

346.33 ES− 345.2 144

342.37 ES+ 343.2 ES− 341.2 145

416.47 ES− 415.2 146

338.40 ES+ 339.2 ES− 337.2 147

338.40 ES+ 339.2 ES− 337.2 148

358.36 ES+ 359.2 ES− 357.2 149

374.82 ES− 373.1/375.1 150

388.85 ES− 387.2/389.2 151

382.46 ES+ 383.2 ES− 381.2 152

338.40 ES+ 339.2 ES− 337.2 153

368.43 ES− 367.2 154

368.43 ES+ 369.2 ES− 367.2 155

382.46 ES− 381.2 156

354.40 ES+ 355.2 ES− 353.2 157

446.34 ES− 445.2 158

378.35 ES+ 379.2 ES− 377.2 159

354.38 ES− 353.2 160

354.38 ES− 353.2 161

344.45 ¹H NMR(300 MHz, CDCl₃) □ppm: 0.9(m, 3H), 1.3(m, 7H), 1.6(m, 2H),2.7(m, 4H), 3.0(m, 2H), 4.2(q, J=7.2Hz, 2H), 4.7(m, 2H), 6.2(d,J=15.8Hz, 1H), 7.1(m, 2H), 7.1(m, 2H), 7.2(s, 1H) 162

316.40 ¹H NMR(300 MHz, CDCl₃) □ppm: 0.9(m, 3H), 1.5(m, 9H), 2.7(m, 4H),3.0(m, 2H), 4.8(m, 2H), 6.2(d, J=15.4Hz, 1H), 7.2(m, 3H) 163

394.51 ES+ 395.3 ES− 393.3 164

505.05 ES− 503.2/505.2 165

360.49 ES+ 361.3 166

358.48 ES+ 359.3 167

344.45 ES+ 345.2 168

330.42 ES+ 331.2 169

354.40 ES+ 355.2 ES− 353.2 170

354.40 ES− 353.2 171

343.37 ES+ 343.2 ES− 341.2 172

338.40 ES+ 339.2 ES− 337.2 173

338.40 ES+ 339.2 ES− 337.2 174

332.44 ES+ 333.3 ES− 331.3 175

356.39 ES+ 357.3 ES− 355.2 176

344.45 ES+ 345.3 ES− 343.3ES− = [M − H]ES+ = [M + H]

1. Compounds of the formula I:

in which: n is an integer chosen from 1, 2 and 3; Y represents O; N—OR⁹,in which R⁹ represents H or a saturated hydrocarbon-based aliphaticgroup; CR¹⁰R¹¹, in which R¹⁰ and R¹¹ which may be identical ordifferent, represent H or a saturated hydrocarbon-based aliphatic group;R¹ and R², which may be identical or different, represent H or asaturated aliphatic hydrocarbon-based chain; or alternatively R¹ and R²together form an optionally substituted saturated aliphatichydrocarbon-based chain; the radicals R³ and R⁴, which may be identicalor different, take any of the meanings given above for R¹ and R², oralternatively R¹ and the group R⁴ borne by the carbon alpha to CR¹R²represent nothing and a double bond links the CR¹R² carbon to the alphaCR³R⁴ carbon; or alternatively one of the radicals R¹ and R² forms withone of the radicals R³ and R⁴ an optionally substituted saturated orunsaturated aliphatic hydrocarbon-based chain; one of the radicals R⁵and R⁶ represents W, and the other represents Z which is chosen from asaturated or unsaturated aliphatic hydrocarbon-based radical; anoptionally substituted, saturated, unsaturated and/or aromaticcarbocyclic or heterocyclic radical; a radical -alk-Cy, in which alkrepresents an alkylene chain and Cy represents an optionally substitutedsaturated, unsaturated and/or aromatic heterocyclic or carbocyclicradical; W represents —XL-CO₂R⁷; —X-L-Tet, in which X and L are asdefined below and Tet represents optionally substituted tetrazole; inwhich L represents a saturated or unsaturated aliphatichydrocarbon-based chain, which is optionally substituted and/oroptionally interrupted by optionally substituted arylene; X representsO; NR⁸, in which R⁸ represents H; a saturated aliphatichydrocarbon-based group; a group —CO—R′ or —SO₂—R′, in which R′ takesany of the meanings given below for R⁷ with the exception of H; or R⁸represents an optionally substituted aromatic carbocyclic group; or Xrepresents S(O)_(m), in which m is chosen from 0, 1 and 2; R⁷ representsH; a saturated or unsaturated aliphatic hydrocarbon-based group; anoptionally substituted, saturated, unsaturated and/or aromaticcarbocyclic group; an optionally substituted, saturated, unsaturatedand/or aromatic heterocyclic group; and the pharmaceutically acceptablederivatives, salts, solvates and stereoisomers thereof, and alsomixtures thereof in all proportions.
 2. Compounds according to claim 1,characterised in that R¹, R², R³ and R⁴ are independently chosen from ahydrogen atom and alkyl.
 3. Compounds according to claim 1,characterised in that n represents 1 or
 2. 4. Compounds according toclaim 1, characterised in that R⁷ represents H or alkyl.
 5. Compoundsaccording to claim 1, characterised in that W represents —X-L-Tet, inwhich Tet represents optionally substituted tetrazolyl.
 6. Compoundaccording to claim 1, characterised in that L represents alkylene,alkenylene or -alk°-Ar°, in which alk° represents alkylene and Ar°represents optionally substituted phenylene.
 7. Compounds according toclaim 6, characterised in that L represents


8. Compounds according to claim 1, characterised in that Z representsalkyl optionally substituted by one or more radicals T; alkenyloptionally substituted by one or more radicals T; alkynyl optionallysubstituted by one or more radicals T; phenyl optionally substituted byone or more radicals T; cycloalkyl optionally substituted by one or moreradicals T; monocyclic or bicyclic heteroaryl optionally substituted byone or more radicals T; -alk¹-Cy¹, in which alk¹ represents alkylene,preferably CH₂ and Cy¹ represents phenyl optionally substituted by oneor more radicals T, or alternatively Cy¹ represents cycloalkyl,optionally substituted by one or more radicals T; T being chosen fromoptionally halogenated alkyl; optionally halogenated alkoxy; a halogenatom; and cyano.
 9. Compounds according to claim 1, characterised inthat n=1; R¹, R², R³ and R⁴ represent a hydrogen atom; Y represents O;R⁵ represents (C₁-C₁₀)alkyl; (C₂-C₁₀)alkynyl; -alk¹-Cy¹, in which alk¹represents (C₁-C₃)alkylene and Cy¹ represents phenyl optionallysubstituted by one or more radicals T, in which T

R⁶ represents W, in which X represents O or NH; and L represents(C₁-C₃)alkylene.
 10. Compounds according to claim 8, characterised inthat X represents NH; and R⁵ represents (C₁-C₁₀)alkyl.
 11. Compoundsaccording to claim 8, characterised in that X represents O; and R⁵represents (C₁-C₁₀)alkyl; (C₂-C₁₀)alkynyl; and -alk¹-Cy¹, in which alk¹represents (C₁-C₃)alkylene and Cy¹ represents phenyl.
 12. Compoundsaccording to claim 8, characterised in that Z represents alkyl,optionally substituted by cyano; phenyl, optionally substituted bytrifluoromethyl, with halogen, with alkyl or with alkoxy; phenylalkyl,in which phenyl is substituted by one or more halogen atoms, alkyl oralkoxy; alkynyl; cycloalkylalkyl.
 13. Compounds according to claim 1,chosen from

and the pharmaceutically acceptable derivatives, salts, solvates andstereoisomers thereof, and also mixtures thereof in all proportions. 14.Pharmaceutical composition comprising an effective amount of at leastone compound chosen from the compounds of the formula I according toclaim 1 and/or the pharmaceutically acceptable derivatives, salts,solvates and stereoisomers thereof, including mixtures thereof in allproportions, in combination with at least one pharmaceuticallyacceptable vehicle.
 15. Medicament comprising at least one compound ofthe formula I according to claim 1 and/or the pharmaceuticallyacceptable derivatives, salts, solvates and stereoisomers thereof, andalso mixtures thereof in all proportions, and optionally one or moreexcipients and/or adjuvants.
 16. Use of a compound of the formula Iaccording to claim 1 and/or the pharmaceutically acceptable derivatives,salts, solvates and stereoisomers thereof, including mixtures thereof inall proportions, for the preparation of a medicament for the treatmentof an individual suffering from a disease or condition mediated by aninsufficiency of activity of the PPARα and PPARγ isoforms in their roleof regulating lipidaemia and glycaemia.
 17. Use, according to claim 16,of compounds of the formula I and/or the physiologically acceptablederivatives, salts, solvates and stereoisomers thereof, includingmixtures thereof in all proportions, for the preparation of a medicamentfor the prevention of or treating dyslipidaemia, atherosclerosis anddiabetes.
 18. Process for the preparation of a compound of the formula Iaccording to claim 1, characterised in that a compound of the formulaII:

in which R¹, R², R³, R⁴, n and Y are as defined above for formula I, Grepresents —XH, in which X is S or O, NHCOCF₃ or NHR⁸, R⁸ being asdefined for formula I in claim 1; and Z° is a radical that is aprecursor of Z, or alternatively Z° represents Z, Z being as defined forformula I in claim 1, Z° and G being in positions 2 and 3 of the phenylnucleus; is reacted with a compound of the formula III:Gp-L-CO₂R⁷  III in which R⁷ and L are as defined in claim 1 for formulaI and Gp represents a leaving group, in the presence of a base. 19.Process for the preparation of a compound of the formula I according toclaim 1, in which Z represents Cy, in which Cy denotes an optionallysubstituted aryl or heteroaryl group, characterised in that it comprisesthe reaction of a compound of the formula IVa:

in which D represents —NHCOCF₃ or —X-L-CO₂R⁷, and L, R⁷, Y, X, R¹, R²,R³, R⁴ and n are as defined for formula I in claim 1, and Hal representsa halogen atom, preferably a bromine or iodine atom, the groups -Hal andD being in position 2 or 3, with an arylboronic or heteroarylboronicacid of the formula V:Cy B(OH)₂  (V) in which the group Cy optionally bears one or moresubstituents, in the presence of a palladium 0 complex and a mineral ororganic base.
 20. Process for the preparation of a compound of theformula I according to, in which Z represents —CH₂-π, in which πrepresents alkyl; alkenyl; alkynyl; Cy¹, Cy¹ being as defined for Cy inclaim 1; or -alk²-Cy¹, alk² representing alkylene and Cy¹ being asdefined above, the said process being characterised in that

a compound of the formula IVa: in which R¹, R², R³, R⁴, n, Y, X, L, R⁷and D are as defined in claim 18 and Hal represents a halogen atom,preferably an iodine or bromine atom, -Hal and D being in position 2 or3, is reacted with a compound of the formula VII(π-CH₂—)ZnBr or (π-CH₂)ZnCl  VII in which π is as defined above, in thepresence of a palladium complex, such asbis(triphenylphosphine)dichloropalladium.
 21. Process for thepreparation of a compound of the formula I in which Y represents N—OH,characterised in that it comprises the reaction of the correspondingcompound of the formula I in which Y═O with a hydroxylamine salt in thepresence of an alkali metal salt.
 22. Process for the preparation of acompound of the formula I in which Y represents CR¹⁰R¹¹, in which R¹⁰and R¹¹ are as defined in claim 1, characterised in that thecorresponding compound of the formula I in which Y represents O isreacted with a compound of the formula IX(C₆H₅)₃P⁺CR¹⁰R¹¹H, Br⁻  IX in the presence of a base.
 23. Compounds ofthe formula II:

in which R¹ and R² are chosen independently from a hydrogen atom and aC₁-C₆ alkyl group, such as methyl; Z° represents I, Br or a C₁-C₁₀ alkylgroup; and G represents —OH; —SH; —NH₂; —OCH₃; —NH—CO—CH₃; —NH—CO—CF₃,the pharmaceutically acceptable derivatives, salts, solvates andstereoisomers thereof, and also mixtures thereof in all proportions. 24.Compounds according to claim 23, chosen from:2,2-dimethyl-5-n-hexyl-6-hydroxyindan-1-one;5-n-hexyl-6-hydroxyindan-1-one; 5-n-hexyl-6-mercaptoindan-1-one;5-iodo-6-methoxyindan-1-one; -bromo-6-aminoindan-1-one;5-bromo-6-hydroxyindan-1-one;2,2-dimethyl-5-n-hexyl-6-methoxyindan-1-one; and5-bromo-6-trifluoromethylcarbonylaminoindan-1-one.
 25. Compounds of theformula IVb²:

in which: R¹ and R² are chosen independently from a hydrogen atom and aC₁-C₆ alkyl group, such as —CH₃; Hal° represents a halogen atom, such asan iodine atom; L and R⁷ are as defined in claim 1, it being understoodthat Hal° and —O-L-CO₂R⁷ are in position 2 or 3, and thepharmaceutically acceptable derivatives, salts, solvates andstereoisomers thereof, and also mixtures thereof in all proportions. 26.Compounds according to claim 25 in which R¹ and R² are hydrogen atoms;Hal° represents a bromine or iodine atom and is in position 2; and—O-L-CO₂R⁷ is in position
 3. 27. Compounds of the formula XXVIIa

in which R¹ and R² represent a hydrogen atom or a (C₁-C₆)alkyl group or—CH₃; Z° is as defined in claim 12 for formula II; and G° representsNO₂, and the pharmaceutically acceptable derivatives, salts, solvatesand stereoisomers thereof, and also mixtures thereof in all proportions.28. Compound according to claim 27, which is 5-bromo-6-nitroindan-1-one.29. Compounds of the formula XX:

in which Q represents C₂-C₁₀ 1-alkynyl, preferably 1-hexynyl, and thepharmaceutically acceptable derivatives, salts, solvates andstereoisomers thereof, and also mixtures thereof in all proportions. 30.Intermediate compounds in the preparation of the compounds of theformula I, chosen from:5-methoxy-6-trifluoromethylsulfonyloxyindan-1-one;5-methoxy-6-bromoindan-1-one; and 5-hydroxy-6-bromoindan-1-one.